Compounds and methods for inhibiting fascin

ABSTRACT

Provided are compounds, compositions and methods for inhibiting fascin activity or treating a condition or disorder mediated by fascin activity in a subject in need thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation U.S. patent application Ser. No.15/851,141, filed on Dec. 21, 2017, which is a continuation of U.S.patent application Ser. No. 15/437,229, filed on Feb. 20, 2017, now U.S.Pat. No. 9,850,243, issued on Dec. 26, 2017, which is a divisional ofU.S. patent application Ser. No. 14/626,791, filed on Feb. 19, 2015, nowU.S. Pat. No. 9,573,946, issued on Feb. 21, 2017, which claims thebenefit of U.S. Provisional Application No. 61/942,554, filed on Feb.20, 2014, the complete disclosures of which is hereby incorporated byreference.

FIELD

The present technology relates generally to compounds, compositions andmethods for treating or preventing cancer.

BACKGROUND

In recent years, progress has been made in the treatment of cancer,particularly with the development of targeted therapeutics. However,there is very little advancement in the treatment of tumor metastasis,which remains the major cause of mortality of cancer patients. Tumormetastasis being responsible for ˜90% of all cancer deaths (1, 2).Metastasis is a multi-step process wherein a primary tumor spreads fromits initial site to secondary tissues and organs (3-5). This metastaticprocess is selective for cells that succeed in cell migration, invasion,embolization, survival in the circulation, arrest in a distant capillarybed, and extravasation into and multiplication within the organparenchyma. Failure at any of these steps could block the entiremetastatic process. Since tumor spreading is responsible for themajority of deaths of cancer patients, there is a demand for thedevelopment of therapeutic agents that inhibit tumor metastasis.

Most current treatments for metastatic cancers are aimed to kill or stopthe growth of primary cancer cells (6-8). Although tumor cell migrationand invasion are critical steps in the process of tumor metastasis(9-12), inhibitors of tumor cell migration are not presently availableto treat metastatic cancer. Therefore, it is desirable to develop smallmolecule inhibitors targeting tumor cell migration.

SUMMARY

In one aspect, the present technology provides compounds of Formula I,Formula Ia, Formula Ib, Formula Ic, Formula Id, or Formula Ie:

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;wherein

-   -   A¹, A², A³, A⁴, A⁵ and A⁶ are independently CH, CR³ or N,        provided that no more than four of A¹, A², A³, A⁴, A⁵ and A⁶ are        N;    -   R¹ is phenyl, 5-membered heteroaryl or 6-membered heteroaryl,        wherein the phenyl, 5-membered heteroaryl or 6-membered        heteroaryl is optionally substituted with 1 to 3 R⁶;    -   L² is selected from the group consisting of a covalent bond,        —NR⁸—, —C(O)NR⁸—, —NR⁸C(O)—, —C(O)CR⁸ ₂—, —CR⁸ ₂C(O)—, —NR⁸CR⁸        ₂—, and —CR⁸ ₂NR⁸—;    -   R² is H, lower alkyl, 6- to 10-membered aryl or 5- to        10-membered heteroaryl; wherein the 6- to 10-membered aryl or 5-        to 10-membered heteroaryl is optionally substituted with 1 to 4        R⁴, wherein each R⁴ is independently selected from the group        consisting of lower alkyl, lower haloalkyl, phenyl (optionally        substituted with lower alkyl, halo, lower haloalkyl, or —OH),        —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰, halo, cyano, nitro, —COH, —COR⁷,        —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰,        —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and        —NR¹⁰SO₂R⁷;    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   m is 0, 1, 2 or 3;    -   q is 1, 2 or 3;    -   each R⁶ is independently selected from the group consisting of        cyano, halo, lower alkyl (such as methyl or ethyl), lower        haloalkyl, and —CH₂OH;    -   R⁷ is lower alkyl (such as methyl or ethyl) or lower haloalkyl;    -   R⁸ is hydrogen or lower alkyl (such as methyl or ethyl);    -   each R¹⁰ is independently hydrogen or lower alkyl (such as        methyl or ethyl), or two R¹⁰ together with the atom(s) attached        thereto form a 4- to 6-membered ring; and    -   R¹ is hydrogen or R³;    -   provided that the compound is not        N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide,        and provided that when L² is a covalent bond, then R² is not H        or lower alkyl.

In some embodiments, the present technology provides a compound selectedfrom Table 1 or a tautomer, and/or pharmaceutically acceptable saltthereof:

TABLE 1 Cmpd Structure Name Inhibition* MS** 1

4,5-dimethyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)furan-2-carboxamide <10% 414 2

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzofuran-2-carboxamide <10% 436 3

5-(p-tolyl)-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)furan-2-carboxamide <10% 476 4

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide   50% 396 5

2-chloro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide  50% 430 6

4-chloro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 430 7

3-chloro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 430 8

6-chloro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)picolinamide<10% 431 9

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiophene-2-carboxamide   60% 402 10

4-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiazole-5-carboxamide   90% 417 11

4-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiazole-2-carboxamide <10% 417 12

2-fluoro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 414 13

4-fluoro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 414 14

3-fluoro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 414 15

2-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 410 16

4-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 410 17

3-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 410 18

4-chloro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)picolinamide<10% 431 19

3,4-difluoro-N-(1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)benzamide <10% 431 20

2,3-difluoro-N-(1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)benzamide <10% 431 21

2,5-difluoro-N-(1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)benzamide <10% 431 22

N,1-bis(4- (trifluoromethyl)benzyl)-1H- indazol-3-amine <10% 450 23

3-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiophene-2-carboxamide <10% 416 24

2-chloro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiazole-4-carboxamide <10% 437 25

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)isoxazole-5-carboxamide 100% 387 26

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)-1H-imidazole-5-carboxamide <10% 386 27

3-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)-1H-pyrrole-2- carboxamide <10% 399 28

4-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)isoxazole-5-carboxamide   80% 401 29

3-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)furan-2-carboxamide <10% 400 30

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiazole-4-carboxamide <10% 403 31

5-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)oxazole-4-carboxamide   60% 401 32

5-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiazole-4-carboxamide <10% 417 33

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)-1,2,5-oxadiazole-3-carboxamide   80% 388 34

4-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)oxazole-5-carboxamide   80% 401 35

3-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)isoxazole-4-carboxamide 100% 401 36

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiazole-5-carboxamide 100% 403 37

3-fluoro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiophene-2-carboxamide <10% 420 38

2-chloro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiophene-3-carboxamide <10% 437 39

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)isothiazole-3-carboxamide   50% 403 40

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)oxazole-5-carboxamide 100% 387 41

3-chloro-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiophene-2-carboxamide <10% 436 42

4-bromo-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)thiophene-3-carboxamide <10% 482 43

2-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)furan-3-carboxamide   90% 400 44

3-methyl-N-(1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)-1H-pyrazole-4- carboxamide   95% 400 45

2-(2-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)acetyl)benzonitrile <10% 421 46

2-bromo-N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)benzamide<10% 475 47

2-(difluoromethoxy)-N-(1- (4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)benzamide <10% 462 48

N-(1-(3- (trifluoromethyl)benzyl)-1H- indazol-3-yl)furan-3- carboxamide<10% 386 49

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)pyridazine-3-carboxamide 100% 398 50

2-(trifluoromethyl)-N-(1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)benzamide <10% 464 51

4-methoxy-N-(1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)thiophene-3- carboxamide <10% 432 52

2-(trifluoromethoxy)-N-(1- (4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)benzamide <10% 480 53

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)pyrazine-2-carboxamide <10% 398 54

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)nicotinamide <10% 39755

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)picolinamide <10% 39756

N-(1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)pyrimidine-5-carboxamide   90% 398 57

N-(1-(2- (trifluoromethyl)benzyl)-1H- indazol-3-yl)furan-3- carboxamide<10% 386 58

N-(1-benzyl-1H-indazol-3- yl)furan-3-carboxamide <10% 318 59

1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-amine <10% 292 60

5-bromo-3-nitro-1-(4- (trifluoromethyl)benzyl)-1H- indazole <10% 400 61

1-benzyl-5-bromo-3-nitro- 1H-indazole <10% 332 62

N-(1H-indazol-3-yl)furan-3- carboxamide <10% 228 63

1-(4-chlorobenzyl)-1H- indazol-3-amine <10% 64

N-(1-(4-chlorobenzyl)-1H- indazol-3-yl)furan-3- carboxamide   50% 65

N-(1-(4-chlorobenzyl)-1H- indazol-3-yl)-3- methylisoxazole-4-carboxamide   90% 66

N-(1-(4-chlorobenzyl)-1H- indazol-3-yl)isoxazole-5- carboxamide 100% 67

N-(1-(4-chlorobenzyl)-1H- indazol-3-yl)-2-methylfuran- 3-carboxamide  50% 68

N-(1-(4-chlorobenzyl)-1H- indazol-3-yl)-4- methylthiazole-5- carboxamide  50% 69

N-(1-(4-chlorobenzyl)-1H- indazol-3-yl)pyridazine-3- carboxamide   50%70

1-(4-fluorobenzyl)-1H- indazol-3-amine <10% 71

N-(1-(4-fluorobenzyl)-1H- indazol-3-yl)furan-3- carboxamide <10% 72

N-(1-(4-fluorobenzyl)-1H- indazol-3-yl)-3- methylisoxazole-4-carboxamide <10% 73

N-(1-(4-fluorobenzyl)-1H- indazol-3-yl)isoxazole-5- carboxamide   50% 74

N-(1-(4-fluorobenzyl)-1H- indazol-3-yl)-2-methylfuran- 3-carboxamide<10% 75

N-(1-(4-fluorobenzyl)-1H- indazol-3-yl)-4- methylthiazole-5- carboxamide<10% 76

N-(1-(4-fluorobenzyl)-1H- indazol-3-yl)pyridazine-3- carboxamide <10% 77

1-(4-methylbenzyl)-1H- indazol-3-amine <10% 78

N-(1-(4-methylbenzyl)-1H- indazol-3-yl)furan-3- carboxamide <10% 79

3-methyl-N-(1-(4- methylbenzyl)-1H-indazol- 3-yl)isoxazole-4-carboxamide <10% 80

N-(1-(4-methylbenzyl)-1H- indazol-3-yl)isoxazole-5- carboxamide   50% 81

2-methyl-N-(1-(4- methylbenzyl)-1H-indazol- 3-yl)furan-3-carboxamide<10% 82

4-methyl-N-(1-(4- methylbenzyl)-1H-indazol- 3-yl)thiazole-5-carboxamide<10% 83

N-(1-(4-methylbenzyl)-1H- indazol-3-yl)pyridazine-3- carboxamide <10% 84

4-((3-amino-1H-indazol-1- yl)methyl)benzonitrile <10% 85

N-(1-(4-cyanobenzyl)-1H- indazol-3-yl)furan-3- carboxamide <10% 86

N-(1-(4-cyanobenzyl)-1H- indazol-3-yl)-3- methylisoxazole-4- carboxamide<10% 87

N-(1-(4-cyanobenzyl)-1H- indazol-3-yl)isoxazole-5- carboxamide <10% 88

N-(1-(4-cyanobenzyl)-1H- indazol-3-yl)-2-methylfuran- 3-carboxamide <10%89

N-(1-(4-cyanobenzyl)-1H- indazol-3-yl)-4- methylthiazole-5- carboxamide<10% 90

N-(1-(4-cyanobenzyl)-1H- indazol-3-yl)pyridazine-3- carboxamide <10% 91

1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3- amine <10%293 92

N-(1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3-yl)furan-3-carboxamide <10% 387 93

3-methyl-N-(1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3-yl)isoxazole-4-carboxamide <10% 402 94

2-methyl-N-(1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3-yl)furan-3-carboxamide <10% 401 95

4-methyl-N-(1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3-yl)thiazole-5-carboxamide <10% 418 96

N-(1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3-yl)pyridazine-3-carboxamide <10% 399 97

3-amino-1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazole-5-carbonitrile <10% 318 98

N-(5-cyano-1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3-yl)furan-3-carboxamide <10% 412 99

N-(5-cyano-1-((6- (trifluoromethyl)pyridin-3-yl)methyl)-1H-indazol-3-yl)- 3-methylisoxazole-4- carboxamide <10% 427100

N-(5-cyano-1-((6- (trifluoromethyl)pyridin-3-yl)methyl)-1H-indazol-3-yl)- 2-methylfuran-3- carboxamide <10% 426 101

N-(5-cyano-1-((6- (trifluoromethyl)pyridin-3-yl)methyl)-1H-indazol-3-yl)- 4-methylthiazole-5- carboxamide <10% 443

N-(5-cyano-1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3-yl)pyridazine-3-carboxamide <10% 424 103

(4-((3-amino-1H-indazol-1- yl)methyl)phenyl)methanol <10% 254 104

N-(1-(4- (hydroxymethyl)benzyl)-1H- indazol-3-yl)furan-3- carboxamide<10% 348 105

N-(1-(4- (trifluoromethyl)benzyl)-1H- indol-3-yl)furan-3- carboxamide<10% 385 106

6-(trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-amine<10% 360 107

N-(6-(trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-3- carboxamide <10% 454 108

3-methyl-N-(6- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)isoxazole-4- carboxamide <10% 469 109

2-methyl-N-(6- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-3- carboxamide <10% 468 110

4-methyl-N-(6- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)thiazole-5- carboxamide <10% 485 111

7-(trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-amine<10% 360 112

N-(7-(trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-3- carboxamide <10% 454 113

3-methyl-N-(7- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)isoxazole-4- carboxamide <10% 469 114

2-methyl-N-(7- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-3- carboxamide <10% 468 115

4-methyl-N-(7- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)thiazole-5- carboxamide <10% 485 116

4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-amine <10% 326 117

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)furan-3-carboxamide <10% 420 118

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)-3-methylisoxazole-4- carboxamide <10% 435 119

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)-2-methylfuran- 3-carboxamide <10% 434 120

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-yl)-4-methylthiazole-5- carboxamide <10% 451 121

N-(4-chloro-1-((6- (trifluoromethyl)pyridin-3- yl)methyl)-1H-indazol-3-yl)pyridazine-3-carboxamide <10% 433 122

5-(trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H- indazol-3-amine<10% 360 123

N-(5-(trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-3- carboxamide <10% 454 124

3-methyl-N-(5- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)isoxazole-4- carboxamide <10% 469 125

2-methyl-N-(5- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-3- carboxamide <10% 468 126

4-methyl-N-(5- (trifluoromethyl)-1-(4- (trifluoromethyl)benzyl)-1H-indazol-3-yl)thiazole-5- carboxamide <10% 485 127

N-(5-(trifluoromethyl)-1-((6- (trifluoromethyl)pyridin-3-yl)methyl)-1H-indazol-3- yl)pyridazine-3-carboxamide <10% 467 128

1-benzyl-N-phenyl-1H- indazole-3-carboxamide <10% 328 129

1-benzyl-N-(thiazol-2-yl)- 1H-indazole-3-carboxamide <10% 335 130

1-benzyl-N-(pyridin-2-yl)- 1H-indazole-3-carboxamide <10% 329 131

6-methyl-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-b]pyridin-3-amine <10% 307 132

N-(6-methyl-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)furan-3-carboxamide <10% 401 133

3-methyl-N-(6-methyl-1-(4- (trifluoromethyl)benzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)isoxazole-4-carboxamide <10% 416 134

2-methyl-N-(6-methyl-1-(4- (trifluoromethyl)benzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)furan-3-carboxamide <10% 415 135

4-methyl-N-(6-methyl-1-(4- (trifluoromethyl)benzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)thiazole-5-carboxamide <10% 432 136

N-(6-methyl-1-((6- (trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)pyridazine-3- carboxamide<10% 136 137

4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-c]pyridin-3-amine 100% 327 138

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)- 4-methylthiazole-5- carboxamide   90% 452139

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridazine-3-carboxamide   90% 433 140

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-c]pyridin-3-yl)furan-3-carboxamide <10% 421 141

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)- 2-methylfuran-3- carboxamide <10% 435 142

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)- 3-methylisoxazole-4- carboxamide <10% 434143

3-bromo-1-(4- (trifluoromethyl)benzyl)-1H- indazole <10% 356 144

3-phenyl-1-(4- (trifluoromethyl)benzyl)-1H- indazole <10% 353 145

3-(naphthalen-1-yl)-1-(4- (trifluoromethyl)benzyl)-1H- indazole <10% 403146

3-(5-methylfuran-2-yl)-1-(4- (trifluoromethyl)benzyl)-1H- indazole <10%357 147

3-(furan-3-yl)-1-(4- (trifluoromethyl)benzyl)-1H- indazole <10% 343 148

3-(2-methylfuran-3-yl)-1-(4- (trifluoromethyl)benzyl)-1H- indazole <10%357 149

4-chloro-N-methyl-1-(4- (trifluoromethyl)benzyl)-1H-pyrazolo[3,4-c]pyridin-3- amine <10% 341 150

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-c]pyridin-3-yl)acetamide <10% 369 151

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-c]pyridin-3-yl)propionamide   80% 383 152

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-c]pyridin-3-yl)isobutyramide 100% 397 153

N-(4-chloro-1-(4- (trifluoromethyl)benzyl)-1H- pyrazolo[3,4-c]pyridin-3-yl)butyramide <10% 397 *measured in terms of the percentage in thereduction of bundle activity in the presence of 50 μM of the compoundrelative to the bundle activity when the compound was not present asdescribed in Example 4 below. **m/z of (M + H)⁺ ion obtained byelectrospray ionization (ESI) mass spectrometry (MS).

In another aspect, the present technology provides a pharmaceuticalcomposition comprising at least one compound described herein.

In still another aspect, the present technology provides a method oftreating a condition or disorder mediated by fascin activity in asubject in need thereof which method comprises administering to thesubject a therapeutically effective amount of at least one compound or acomposition described herein.

In another aspect, the present technology provides a method ofinhibiting fascin activity, comprising administering an effective amountof a compound or a composition described herein to a cell in needthereof to thereby inhibit fascin activity in the cell.

In another aspect, the present technology provides a compound or acomposition described herein for use in inhibiting fascin activity or intreating a condition or disorder mediated by fascin activity in asubject in need thereof.

In another aspect, the present technology provides use of a compound ora composition described herein in the preparation of a medicament fortreating a condition or disorder mediated by fascin activity in asubject in need thereof or for inhibiting fascin activity.

In some embodiments, the cell is in an animal. In some embodiments, thecell has been removed from an animal. In some embodiments, the animal isa human. In some embodiments, the human suffers from a disease orcondition.

In some embodiments, the condition or disorder is a metastatic cancer, aneuronal disorder, neuronal degeneration, an inflammatory condition, aviral infection, a bacterial infection, lymphoid hyperplasia, Hodgkin'sdisease or ischemia-related tissue damage. In some embodiments, thecondition or disorder is a metastatic cancer.

In some embodiments, the cancer is a carcinoma, lymphoma, sarcoma,melanoma, astrocytoma, mesothelioma cells, ovarian carcinoma, coloncarcinoma, pancreatic carcinoma, esophageal carcinoma, stomachcarcinoma, lung carcinoma, urinary carcinoma, bladder carcinoma, breastcancer, gastric cancer, leukemia, lung cancer, colon cancer, centralnervous system cancer, melanoma, ovarian cancer, renal cancer orprostate cancer.

In still another aspect, the present technology provides methods andintermediate compounds for the preparation of compounds of Formula I ortautomer thereof, and/or a pharmaceutically acceptable salt thereof. Insome embodiments, the intermediate compounds are of any of the followingFormulas

wherein

-   -   A¹, A², A³, A⁴, A⁵ and A⁶ are independently CH, CR³ or N,        provided that no more than four of A¹, A², A³, A⁴, A⁵ and A⁶ are        N;    -   A⁷ is NH or CH₂;    -   Y is F, Cl, Br or I;    -   R¹ is phenyl, 5-membered heteroaryl or 6-membered heteroaryl,        wherein the phenyl, 5-membered heteroaryl or 6-membered        heteroaryl is optionally substituted with 1 to 3 R⁶;    -   R² is 6- to 10-membered aryl or 5- to 10-membered heteroaryl;        wherein the 6- to 10-membered aryl or 5- to 10-membered        heteroaryl is optionally substituted with 1 to 4 R⁴, wherein        each R⁴ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, phenyl (optionally substituted        with lower alkyl, halo, lower haloalkyl, or —OH), —OH, —OR⁷,        —SH, —SR⁷, —NR¹⁰R¹⁰, halo, cyano, nitro, —COH, —COR⁷, —CO₂H,        —CO₂R⁷, —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷,        —NR¹⁰CO₂R⁷, —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   m is 0, 1, 2 or 3;    -   q is 1, 2 or 3;    -   each R⁶ is independently selected from the group consisting of        cyano, halo, lower alkyl (such as methyl or ethyl) and lower        haloalkyl;    -   R⁷ is lower alkyl (such as methyl or ethyl) or lower haloalkyl;    -   R¹¹ is hydrogen or R³; and    -   each R¹⁰ is independently hydrogen or lower alkyl (such as        methyl or ethyl), or two R¹⁰ together with the atom(s) attached        thereto form a 4- to 6-membered ring.

DETAILED DESCRIPTION

The illustrative embodiments described in the detailed description, andclaims are not meant to be limiting. Other embodiments may be utilized,and other changes may be made, without departing from the spirit orscope of the subject matter presented here.

Fascin is an actin-bundling protein. For cell migration to proceed,actin cytoskeleton must be reorganized by forming polymers and bundlesto affect the dynamic changes of cell shapes (References 13-15).Individual actin filaments are flexible and elongation of individualfilaments per se is insufficient for membrane protrusion which isnecessary for cell migration. Bundling of actin filaments providesrigidity to actin filaments for protrusions in the form of lamellipodiaand filopodia against the compressive force from the plasma membrane(Reference 16) (Reference 17). As noted, one of the criticalactin-bundling proteins is fascin (References 18-22). Fascin is theprimary actin cross-linker in filopodia and shows no sequence homologywith other actin-binding proteins (Reference 23). It is required tomaximally cross-link the actin filaments into straight, compact, andrigid bundles (Reference 24).

Elevated levels of fascin have been found in many types of metastatictumors (including breast, prostate, ovarian, lung, gastric, esophageal,and others) and are correlated with clinically aggressive phenotypes,poor prognosis, and shorter survival (References 25-29) (References 30,31) (References 32-34). Fascin inhibitors may target tumor cellmigration and invasion, and provide treatments for metastatic cancer.

Definitions

The technology is described herein using several definitions, as setforth throughout the specification.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the elements (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext.

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent depending upon the context inwhich it is used. If there are uses of the term which are not clear topersons of ordinary skill in the art, given the context in which it isused, “about” will mean up to plus or minus 10% of the particular term.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined herein. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

“Alkyl” encompasses straight chain and branched chain having theindicated number of carbon atoms, usually from 1 to 20 carbon atoms, forexample 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For exampleC₁-C₆ alkyl encompasses both straight and branched chain alkyl of from 1to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and thelike. Alkylene is another subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment. Alkylene groupswill usually have from 2 to 20 carbon atoms, for example 2 to 8 carbonatoms, such as from 2 to 6 carbon atoms. For example, C₀ alkyleneindicates a covalent bond and C₁ alkylene is a methylene group. When analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, “butyl” is meant to include n-butyl,sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl andisopropyl. “Lower alkyl” refers to an alkyl group having 1 to 4 carbons.

“Alkenyl” refers to straight or branched hydrocarbyl groups having theindicated number of carbon atoms, usually from 1 to 8 carbon atoms, forexample 2 to 4 carbon atoms, and at least 1 and preferably from 1 to 2sites of vinyl (>C═C<) unsaturation. Such groups are exemplified, forexample, by vinyl, allyl, and but-3-en-1-yl. Included within this termare the cis and trans isomers or mixtures of these isomers. “Loweralkenyl” refers to an alkenyl group having 1 to 4 carbons, which can beindicated by C₂-C₄ alkenyl.

“Cycloalkyl” indicates a non-aromatic partially saturated, or fullysaturated carbocyclic ring having the indicated number of carbon ringatoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms.Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic,tricyclic). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl, as well asbridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane).In addition, one ring of a polycyclic cycloalkyl group may be aromatic,provided the polycyclic cycloalkyl group is bound to the parentstructure via a non-aromatic carbon. For example, a1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is a cycloalkylgroup, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety isbound to the parent structure via an aromatic carbon atom) is notconsidered a cycloalkyl group. Examples of polycyclic cycloalkyl groupsconsisting of a cycloalkyl group fused to an aromatic ring are describedbelow.

“Aryl” indicates an aromatic carbon ring having the indicated number ofcarbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms, in the ring.Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).In some instances, both rings of a polycyclic aryl group are aromatic(e.g., naphthyl). In other instances, polycyclic aryl groups may includea non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to an aromatic ring, provided the polycyclicaryl group is bound to the parent structure via an atom in the aromaticring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein themoiety is bound to the parent structure via an aromatic carbon atom) isconsidered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl(wherein the moiety is bound to the parent structure via a non-aromaticcarbon atom) is not considered an aryl group. Similarly, a1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound tothe parent structure via an aromatic carbon atom) is considered an arylgroup, while 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moietyis bound to the parent structure via a non-aromatic nitrogen atom) isnot considered an aryl group. However, the term “aryl” does notencompass or overlap with “heteroaryl”, as defined herein, regardless ofthe point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl areheteroaryl groups). In some instances, aryl is phenyl or naphthyl. Incertain instances, aryl is phenyl. Additional examples of aryl groupscomprising an aromatic carbon ring fused to a non-aromatic ring aredescribed below.

“Carboxy” or “carboxyl” refers to —COOH or a salt thereof.

“Heteroaryl” indicates an aromatic ring containing the indicated numberof ring atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up ofone or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected fromN, O and S and with the remaining ring atoms being carbon. 5-Memberedheteroaryl is a heteroaryl having 5 ring atoms. 6-Membered heteroaryl isa heteroaryl having 6 ring atoms. Heteroaryl groups do not containadjacent S and O atoms. In some embodiments, the total number of S and Oatoms in the heteroaryl group is not more than 2. In some embodiments,the total number of S and O atoms in the heteroaryl group is not morethan 1. Unless otherwise indicated, heteroaryl groups may be bound tothe parent structure by a carbon or nitrogen atom, as valency permits.For example, “pyridyl” includes 2-pyridyl, 3-pyridyl and 4-pyridylgroups, and “pyrrolyl” includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolylgroups. When nitrogen is present in a heteroaryl ring, it may, where thenature of the adjacent atoms and groups permits, exist in an oxidizedstate (i.e., N⁺—O⁻). Additionally, when sulfur is present in aheteroaryl ring, it may, where the nature of the adjacent atoms andgroups permits, exist in an oxidized state (i.e., S⁺—O⁻ or SO₂).Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic,tricyclic).

In some instances, a heteroaryl group is monocyclic. Examples includepyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole,1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole,oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole),thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine,pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

In some instances, both rings of a polycyclic heteroaryl group arearomatic. Examples include indole, isoindole, indazole, benzoimidazole,benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole,benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole,1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine,3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine,1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine,3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine,1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine,1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine,furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine,[1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine,oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine,[1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine,oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine,[1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine,oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine,[1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine,thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine,[1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine,thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine,[1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine,thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine,[1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine,thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine,[1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, phthalazine, naphthyridine (e.g.,1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine,1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine),imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole,1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

In other instances, polycyclic heteroaryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclicheteroaryl group is bound to the parent structure via an atom in thearomatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylgroup (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered a heteroaryl group, while4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is not considered aheteroaryl group. Examples of polycyclic heteroaryl groups consisting ofa heteroaryl ring fused to a non-aromatic ring are described below.

“Heterocycloalkyl” indicates a non-aromatic partially saturated, orfully saturated ring having the indicated number of ring atoms (e.g., 3to 10, or 3 to 7, membered heterocycloalkyl) made up of one or moreheteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and Sand with the remaining ring atoms being carbon. 5-Memberedheterocycloalkyl is a heterocycloalkyl having 5 ring atoms. 6-Memberedheterocycloalkyl is a heterocycloalkyl having 6 ring atoms.Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic,tricyclic). Examples of heterocycloalkyl groups include oxiranyl,aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. When nitrogenis present in a heterocycloalkyl ring, it may, where the nature of theadjacent atoms and groups permits, exist in an oxidized state (i.e.,N⁺—O⁻). Examples include piperidinyl N-oxide and morpholinyl-N-oxide.Additionally, when sulfur is present in a heterocycloalkyl ring, it may,where the nature of the adjacent atoms and groups permits, exist in anoxidized state (i.e., S⁺—O⁻ or —SO₂—). Examples include thiomorpholineS-oxide and thiomorpholine S,S-dioxide. In addition, one ring of apolycyclic heterocycloalkyl group may be aromatic (e.g., aryl orheteroaryl), provided the polycyclic heterocycloalkyl group is bound tothe parent structure via a non-aromatic carbon or nitrogen atom. Forexample, a 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety isbound to the parent structure via a non-aromatic nitrogen atom) isconsidered a heterocycloalkyl group, while1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound tothe parent structure via an aromatic carbon atom) is not considered aheterocycloalkyl group. Examples of polycyclic heterocycloalkyl groupsconsisting of a heterocycloalkyl group fused to an aromatic ring aredescribed below.

By “alkoxy” is meant an alkyl group of the indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,3-methylpentoxy, and the like. An alkoxy group is further meant toencompass a cycloalkyl group, as defined above, that is likewiseattached through an oxygen bridge. Alkoxy groups will usually have from1 to 6 carbon atoms attached through the oxygen bridge. “Lower alkoxy”refers to an alkoxy group having 1 to 4 carbons.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

“Haloalkyl” refers to alkyl groups substituted with 1 to 5, 1 to 3, or 1to 2 halo groups, wherein alkyl and halo are as defined herein. Lowerhaloalkyl refers to a C₁-C₄ alkyl substituted with 1 to 5, 1 to 3, or 1to 2 halo groups.

“Lower alkylphenyl” refers to C₁-C₄ alkyl-phenyl.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The symbol “(±)” may be used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. A “meso compound” or “meso isomer” is anon-optically active member of a set of stereoisomers. Meso isomerscontain two or more stereocenters but are not chiral (i.e., a plane ofsymmetry exists within the molecule). The absolute stereochemistry isspecified according to the Cahn-Ingold-Prelog R—S system. When acompound is a pure enantiomer the stereochemistry at each chiral carboncan be specified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdisclosed and/or described herein contain one or more asymmetric centersand can thus give rise to enantiomers, diastereomers, meso isomers andother stereoisomeric forms. Unless otherwise indicated, compoundsdisclosed and/or described herein include all such possible enantiomers,diastereomers, meso isomers and other stereoisomeric forms, includingracemic mixtures, optically pure forms and intermediate mixtures.Enantiomers, diastereomers, meso isomers and other stereoisomeric formscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. Unless specified otherwise, when thecompounds disclosed and/or described herein contain olefinic doublebonds or other centers of geometric asymmetry, it is intended that thecompounds include both E and Z isomers.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. Tautomerization is a form of isomerization and includesprototropic or proton-shift tautomerization, which is considered asubset of acid-base chemistry. Prototropic tautomerization orproton-shift tautomerization involves the migration of a protonaccompanied by changes in bond order, often the interchange of a singlebond with an adjacent double bond. Where tautomerization is possible(e.g. in solution), a chemical equilibrium of tautomers can be reached.An example of tautomerization is keto-enol tautomerization. A specificexample of keto-enol tautomerization is the interconverision ofpentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Anotherexample of tautomerization is phenol-keto tautomerization. A specificexample of phenol-keto tautomerization is the interconversion ofpyridin-4-ol and pyridin-4(1H)-one tautomers. When the compoundsdescribed herein contain moieties capable of tautomerization, and unlessspecified otherwise, it is intended that the compounds include allpossible tautomers.

Pharmaceutically acceptable forms of the compounds recited hereininclude pharmaceutically acceptable salts, and mixtures thereof.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

The compounds disclosed and/or described herein can be enriched isotopicforms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. Inone embodiment, the compound contains at least one deuterium atom. Suchdeuterated forms can be made, for example, by the procedure described inU.S. Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds mayimprove the efficacy and increase the duration of action of compoundsdisclosed and/or described herein. Deuterium substituted compounds canbe synthesized using various methods, such as those described in: Dean,D., Recent Advances in the Synthesis and Applications of RadiolabeledCompounds for Drug Discovery and Development, Curr. Pharm. Des., 2000;6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds viaOrganometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; andEvans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem.,1981, 64(1-2), 9-32.

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules.

The term “active agent” is used to indicate a substance which hasbiological activity. In some embodiments, an “active agent” is asubstance having pharmaceutical utility. For example an active agent maybe an anti-metastasis therapeutic.

The term “therapeutically effective amount” or “effective amount” meansan amount effective, when administered to a human or non-human subject,to provide a therapeutic benefit such as amelioration of symptoms,slowing of disease progression, or prevention of disease, or to inhibitfascin activity in vitro or in vivo, e.g., a therapeutically effectiveamount may be an amount sufficient to decrease the symptoms of a diseaseresponsive to inhibition of fascin activity.

“Inhibition of fascin activity” refers to a decrease in fascin activityas a direct or indirect response to the presence of at least onecompound, or pharmaceutically acceptable salt thereof, described herein,relative to the activity of fascin in the absence of the at least onecompound, or pharmaceutically acceptable salt thereof, described herein.The decrease in activity may be due to the direct interaction of the atleast one compound, or pharmaceutically acceptable salt thereof,described herein with fascin or with one or more other factors that inturn affect fascin activity.

In some embodiments, the compound, or pharmaceutically acceptable saltthereof, described herein has an IC₅₀ (the concentration that inhibits50% of fascin activity) value of about 500 micromolar, about 100micromolar, about 10 micromolar, about 1 micromolar, about 500nanomolar, about 400 nanomolar, about 300 nanomolar, about 200nanomolar, about 100 nanomolar, about 50 nanomolar, about 10 nanomolar,of less than about 10 nanomolar, or a range between and including anytwo of these values.

A “disease responsive to inhibition of fascin activity” is a disease inwhich inhibiting fascin provides a therapeutic benefit such as anamelioration of symptoms, decrease in disease progression, prevention ordelay of disease onset, prevention or amelioration of an inflammatoryresponse, or inhibition of aberrant activity and/or death of certaincell-types (such as cancer cells).

“Treatment” or “treating” means any treatment of a disease in a patient,including:

-   -   a) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   b) inhibiting the progression of the disease;    -   c) slowing or arresting the development of clinical symptoms;        and/or    -   d) relieving the disease, that is, causing the regression of        clinical symptoms.

“Subject” or “patient’ refers to an animal, such as a mammal, that hasbeen or will be the object of treatment, observation or experiment. Themethods described herein may be useful in both human therapy andveterinary applications. In some embodiments, the subject is a mammal;and in some embodiments the subject is human.

As used herein, the term “cancer” includes solid mammalian tumors aswell as hematological malignancies. The terms “tumor cell(s)” and“cancer cell(s)” are used interchangeably herein.

“Solid mammalian tumors” include cancers of the head and neck, lung,mesothelioma, mediastinum, esophagus, stomach, pancreas, hepatobiliarysystem, small intestine, colon, colorectal, rectum, anus, kidney,urethra, bladder, prostate, urethra, penis, testis, gynecologicalorgans, ovaries, breast, endocrine system, skin, central nervous system;sarcomas of the soft tissue and bone; and melanoma of cutaneous andintraocular origin.

The term “hematological malignancies” includes childhood leukemia andlymphomas, Hodgkin's disease, lymphomas of lymphocytic and cutaneousorigin, acute and chronic leukemia, plasma cell neoplasm and cancersassociated with AIDS.

Also, in these examples and elsewhere, abbreviations have the followingmeanings:

-   -   ° C.=degree Celsius    -   μL=microliter    -   μM=micromolar    -   DDT=dithiothreitol    -   DMSO=dimethyl sulfoxide    -   g=gram    -   kg=kilogram    -   hr or h=hour    -   L=liter    -   M=molar    -   nM=nanomolar    -   mg=milligram    -   MHz=mega Hertz    -   min=minute    -   mL=milliliter    -   mm=millimeter    -   mM=millimolar    -   mmol=millimole    -   mol=mole    -   PMSF=phenylmethylsulfonyl fluoride    -   N=normal    -   EDTA=ethylenediaminetetraacetic acid    -   μm=micrometer    -   r.p.m=round per minute    -   S.D.=standard deviation    -   v/v=volume/volume    -   wt=weight        Compounds

The present technology provides compounds of Formula I, Ia or Ib:

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;wherein

-   -   A¹, A², A³, A⁴, A⁵ and A⁶ are independently CH, CR³ or N,        provided that no more than four of A¹, A², A³, A⁴, A⁵ and A⁶ are        N;    -   R¹ is phenyl, 5-membered heteroaryl or 6-membered heteroaryl,        wherein the phenyl, 5-membered heteroaryl or 6-membered        heteroaryl is optionally substituted with 1 to 3 R⁶;    -   L² is selected from the group consisting of —NR⁸—, —C(O)NR⁸—,        —NR⁸C(O)—, —C(O)CR⁸ ₂—, —CR⁸ ₂C(O)—, —NR⁸CR⁸ ₂—, and —CR⁸ ₂NR⁸—;    -   R² is hydrogen, lower alkyl, 6- to 10-membered aryl or 5- to        10-membered heteroaryl; wherein the 6- to 10-membered aryl or 5-        to 10-membered heteroaryl is optionally substituted with 1 to 4        R⁴, wherein each R⁴ is independently selected from the group        consisting of lower alkyl, lower haloalkyl, phenyl (optionally        substituted with lower alkyl, halo, lower haloalkyl, or —OH),        —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰, halo, cyano, nitro, —COH, —COR⁷,        —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰,        —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and        —NR¹⁰SO₂R⁷;    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   m is 0, 1, 2 or 3;    -   q is 1, 2 or 3;    -   each R⁶ is independently selected from the group consisting of        cyano, halo, lower alkyl (such as methyl or ethyl), lower        haloalkyl, and —CH₂OH;    -   R⁷ is lower alkyl (such as methyl or ethyl) or lower haloalkyl;    -   R⁸ is hydrogen or lower alkyl (such as methyl or ethyl);    -   each R¹⁰ is independently hydrogen or lower alkyl (such as        methyl or ethyl), or two R¹⁰ together with the atom(s) attached        thereto form a 4- to 6-membered ring; and    -   R¹ is hydrogen or R³;    -   provided that the compound is not        N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

The present technology provides compounds of Formula I, Ia or Ib:

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;wherein

-   -   A¹, A², A³, A⁴, A⁵ and A⁶ are independently CH, CR³ or N,        provided that no more than four of A¹, A², A³, A⁴, A⁵ and A⁶ are        N;    -   R¹ is phenyl, 5-membered heteroaryl or 6-membered heteroaryl,        wherein the phenyl, 5-membered heteroaryl or 6-membered        heteroaryl is optionally substituted with 1 to 3 R⁶;    -   L² is selected from the group consisting of —C(O)NR⁸—,        —NR⁸C(O)—, —C(O)CR⁸ ₂—, —CR⁸ ₂C(O)—, —NR⁸CR⁸ ₂—, and —CR⁸ ₂NR⁸—;    -   R² is 6- to 10-membered aryl or 5- to 10-membered heteroaryl;        wherein the 6- to 10-membered aryl or 5- to 10-membered        heteroaryl is optionally substituted with 1 to 4 R⁴, wherein        each R⁴ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, phenyl (optionally substituted        with lower alkyl, halo, lower haloalkyl, or —OH), —OH, —OR⁷,        —SH, —SR⁷, —NR¹⁰R¹⁰, halo, cyano, nitro, —COH, —COR⁷, —CO₂H,        —CO₂R⁷, —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷,        —NR¹⁰CO₂R⁷, —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   m is 0, 1, 2 or 3;    -   q is 1, 2 or 3;    -   each R⁶ is independently selected from the group consisting of        cyano, halo, lower alkyl (such as methyl or ethyl), lower        haloalkyl, and —CH₂OH;    -   R⁷ is lower alkyl (such as methyl or ethyl) or lower haloalkyl;    -   R⁸ is hydrogen or lower alkyl (such as methyl or ethyl);    -   each R¹⁰ is independently hydrogen or lower alkyl (such as        methyl or ethyl), or two R¹⁰ together with the atom(s) attached        thereto form a 4- to 6-membered ring; and    -   R¹¹ is hydrogen or R³;    -   provided that the compound is not        N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

In some embodiments, R⁸ is hydrogen. In some embodiments, q is 1.

In some embodiments, provided is a compound of Formula II

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;wherein

-   -   R¹ is phenyl, 5-membered heteroaryl or 6-membered heteroaryl,        wherein the phenyl, 5-membered heteroaryl or 6-membered        heteroaryl is optionally substituted with 1 to 3 R⁶;    -   L² is selected from the group consisting of —C(O)NH—, —NHC(O)—,        —C(O)CH₂—, —CH₂C(O)—, —NHCH₂—, and —CH₂NH—;    -   R² is 6- to 10-membered aryl or 5- to 10-membered heteroaryl;        wherein the 6- to 10-membered aryl or 5- to 10-membered        heteroaryl is optionally substituted with 1 to 4 R⁴, wherein        each R⁴ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, phenyl (optionally substituted        with lower alkyl, halo or lower haloalkyl, or —OH), —OH, —OR⁷,        —SH, —SR⁷, —NR¹⁰R¹⁰, halo, cyano, nitro, —COH, —COR⁷, —CO₂H,        —CO₂R⁷, —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷,        —NR¹⁰CO₂R⁷, —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR¹⁰, —NR¹⁰CO₂R¹⁰, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   m is 0, 1, 2 or 3;    -   n is 0, 1, 2 or 3;    -   q is 1, 2 or 3;    -   each R⁶ is independently selected from the group consisting of        halo, cyano, lower alkyl (preferably methyl or ethyl) and lower        haloalkyl;    -   R⁷ is lower alkyl (preferably methyl or ethyl) or lower        haloalkyl; and    -   each R¹⁰ is independently hydrogen or lower alkyl (preferably        methyl or ethyl), or two R¹⁰ together with the atom(s) attached        thereto form a 4- to 6-membered ring;    -   provided that the compound is not        N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

In some embodiments, provided is a compound of Formula IIIa, IIIb, IIIcor IIId

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;wherein

-   -   R² is 6- to 10-membered aryl or 5- to 10-membered heteroaryl;        wherein the 6- to 10-membered aryl or 5- to 10-membered        heteroaryl is optionally substituted with 1 to 4 R⁴, wherein        each R⁴ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, phenyl (optionally substituted        with lower alkyl, halo or lower haloalkyl, or —OH), —OH, —OR⁷,        —SH, —SR⁷, —NR¹⁰R¹⁰, halo, cyano, nitro, —COH, —COR⁷, —CO₂H,        —CO₂R⁷, —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷,        —NR¹⁰CO₂R⁷, —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   m is 0, 1, 2 or 3;    -   n is 0, 1, 2 or 3;    -   each R⁶ is independently selected from the group consisting of        halo, cyano, lower alkyl (preferably methyl or ethyl) and lower        haloalkyl;    -   R⁷ is lower alkyl (preferably methyl or ethyl); and    -   each R¹⁰ is independently hydrogen or lower alkyl (preferably        methyl or ethyl), or two R¹⁰ together with the atom(s) attached        thereto form a 4- to 6-membered ring;    -   provided that the compound is not        N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

In some embodiments, provided is a compound of Formula IVa, IVb, IVc orIVd:

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;wherein

-   -   R² is 6- to 10-membered aryl or 5- to 10-membered heteroaryl;        wherein the 6- to 10-membered aryl or 5- to 10-membered        heteroaryl is optionally substituted with 1 to 4 R⁴, wherein        each R⁴ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR¹⁰, —NR¹⁰CO₂R¹⁰, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, phenyl (optionally substituted with lower        alkyl, halo or lower haloalkyl, or —OH), and —NR¹⁰SO₂R⁷;    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR¹⁰, —NR¹⁰CO₂R¹⁰, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   m is 0, 1, 2 or 3;    -   R⁷ is lower alkyl (preferably methyl or ethyl); and    -   each R¹⁰ is independently hydrogen or lower alkyl (preferably        methyl or ethyl), or two R¹⁰ together with the atom(s) attached        thereto form a 4- to 6-membered ring;    -   provided that the compound is not        N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

In another aspect, the present technology provides intermediatecompounds for the preparation of compounds of Formula I or tautomerthereof, and/or a pharmaceutically acceptable salt thereof. In someembodiments, the intermediate compounds are of any of the followingFormulas

wherein

-   -   A¹, A², A³, A⁴, A⁵ and A⁶ are independently CH, CR³ or N,        provided that no more than four of A¹, A², A³, A⁴, A⁵ and A⁶ are        N;    -   A⁷ is NH or CH₂;    -   Y is F, Cl, Br or I;    -   R¹ is phenyl, 5-membered heteroaryl or 6-membered heteroaryl,        wherein the phenyl, 5-membered heteroaryl or 6-membered        heteroaryl is optionally substituted with 1 to 3 R⁶;    -   R² is 6- to 10-membered aryl or 5- to 10-membered heteroaryl;        wherein the 6- to 10-membered aryl or 5- to 10-membered        heteroaryl is optionally substituted with 1 to 4 R⁴, wherein        each R⁴ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, phenyl (optionally substituted        with lower alkyl, halo, lower haloalkyl, or —OH), —OH, —OR⁷,        —SH, —SR⁷, —NR¹⁰R¹⁰, halo, cyano, nitro, —COH, —COR⁷, —CO₂H,        —CO₂R⁷, —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷,        —NR¹⁰CO₂R⁷, —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷;    -   m is 0, 1, 2 or 3;    -   q is 1, 2 or 3;    -   each R⁶ is independently selected from the group consisting of        cyano, halo, lower alkyl (such as methyl or ethyl) and lower        haloalkyl;    -   R⁷ is lower alkyl (such as methyl or ethyl) or lower haloalkyl;    -   R¹¹ is hydrogen or R³; and    -   each R¹⁰ is independently hydrogen or lower alkyl (such as        methyl or ethyl), or two R¹⁰ together with the atom(s) attached        thereto form a 4- to 6-membered ring.

The present technology provides compounds of Formula VIII, VIIIa orVIIIb:

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;wherein

-   -   L² is selected from the group consisting of —NR⁸—, —C(O)NR⁸—,        —NR⁸C(O)—, —C(O)CR⁸ ₂—, —CR⁸ ₂C(O)—, —NR⁸CR⁸ ₂—, and —CR⁸ ₂NR⁸—;    -   R^(2a) is hydrogen, or —NHC(O)R², wherein R² is lower alkyl,        6-membered aryl or 5- to 10-membered heteroaryl; wherein the 6-        to 10-membered aryl or 5- to 10-membered heteroaryl is        optionally substituted with 1 to 4 R⁴, wherein each R⁴ is        independently selected from the group consisting of lower alkyl,        lower haloalkyl, phenyl (optionally substituted with lower        alkyl, halo, lower haloalkyl, or —OH), —OH, —OR⁷, —SH, —SR⁷,        —NR¹⁰R¹⁰, halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷,        —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷,        —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷; and    -   each R³ is independently selected from the group consisting of        lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, —NR¹⁰R¹⁰,        halo, cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰,        —OCOR⁷, —OCO₂R⁷, —OCONR¹⁰R¹⁰, —NR¹⁰COR⁷, —NR¹⁰CO₂R⁷, —SOR⁷,        —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and —NR¹⁰SO₂R⁷.

In some embodiments, L² is —C(O)NH—, —C(O)CH₂—, or —CH₂NH—.

In some embodiments, A¹ is N and A², A³, A⁴, A⁵ and A⁶ are independentlyCH or CR³. In some embodiments, A² is N and A¹, A³, A⁴, A⁵ and A⁶ areindependently CH or CR³. In some embodiments, A³ is N and A¹, A², A⁴, A⁵and A⁶ are independently CH or CR³. In some embodiments, A⁴ is N and A¹,A², A³, A⁵ and A⁶ are independently CH or CR³. In some embodiments, A⁵is N and A¹, A², A³, A⁴, and A⁶ are independently CH or CR³. In someembodiments, A⁶ is N and A¹, A², A³, A⁴, and A⁵ are independently CH orCR³.

In some embodiments, A¹ and A² are N. In some embodiments, A³, A⁴, A⁵and A⁶ are independently CH or CR³. In some embodiments, A³ is N, andA⁴, A⁵ and A⁶ are independently CH or CR³. In some embodiments, A⁴ is Nand A³, A⁵ and A⁶ are independently CH or CR³. In some embodiments, A⁵is N, and A³, A⁴ and A⁶ are independently CH or CR³. In someembodiments, A⁶ is N, and A³, A⁴, and A⁵ are independently CH or CR³. Insome embodiments, A³ and A⁴ are N, and A⁵ and A⁶ are independently CH orCR³. In some embodiments, A³ and A⁵ are N, and A⁴ and A⁶ areindependently CH or CR³. In some embodiments, A³ and A⁶ are N, and A⁴and A⁵ are independently CH or CR³. In some embodiments, A⁴ and A⁵ areN, and A³ and A⁶ are independently CH or CR³. In some embodiments, A⁴and A⁶ are N, and A³ and A⁵ are independently CH or CR³. In someembodiments, A⁵ and A⁶ are N, and A³ and A⁴ are independently CH or CR³.

In some embodiments, A¹ and A³ are N. In some embodiments, A², A⁴, A⁵and A⁶ are independently CH or CR³. In some embodiments, A⁴ is N, andA², A⁵ and A⁶ are independently CH or CR³. In some embodiments, A⁵ is Nand A², A⁴ and A⁶ are independently CH or CR³. In some embodiments, A⁶is N, and A², A⁴ and A⁵ are independently CH or CR³. In someembodiments, A² and A⁴ are N, and A⁵ and A⁶ are independently CH or CR³.In some embodiments, A² and A⁵ are N, and A⁴ and A⁶ are independently CHor CR³. In some embodiments, A² and A⁶ are N, and A⁴ and A⁵ areindependently CH or CR³. In some embodiments, A⁴ and A⁵ are N, and A²and A⁶ are independently CH or CR³. In some embodiments, A⁴ and A⁶ areN, and A² and A⁵ are independently CH or CR³. In some embodiments, A⁵and A⁶ are N, and A² and A⁴ are independently CH or CR³.

In some embodiments, A¹ and A⁴ are N. In some embodiments, A², A³, A⁵and A⁶ are independently CH or CR³. In some embodiments, A³ is N, andA², A⁵ and A⁶ are independently CH or CR³. In some embodiments, A⁵ is Nand A², A³ and A⁶ are independently CH or CR³. In some embodiments, A⁶is N, and A², A³ and A⁵ are independently CH or CR³. In someembodiments, A² and A³ are N, and A⁵ and A⁶ are independently CH or CR³.In some embodiments, A² and A⁵ are N, and A³ and A⁶ are independently CHor CR³. In some embodiments, A² and A⁶ are N, and A³ and A⁵ areindependently CH or CR³. In some embodiments, A³ and A⁵ are N, and A²and A⁶ are independently CH or CR³. In some embodiments, A³ and A⁶ areN, and A² and A⁵ are independently CH or CR³. In some embodiments, A⁵and A⁶ are N, and A² and A³ are independently CH or CR³.

In some embodiments, A¹ and A⁵ are N. In some embodiments, A², A⁴, A³and A⁶ are independently CH or CR³. In some embodiments, A⁴ is N, andA², A³ and A⁶ are independently CH or CR³. In some embodiments, A³ is Nand A², A⁴ and A⁶ are independently CH or CR³. In some embodiments, A⁶is N, and A², A⁴ and A³ are independently CH or CR³. In someembodiments, A² and A⁴ are N, and A³ and A⁶ are independently CH or CR³.In some embodiments, A² and A³ are N, and A⁴ and A⁶ are independently CHor CR³. In some embodiments, A² and A⁶ are N, and A⁴ and A³ areindependently CH or CR³. In some embodiments, A⁴ and A³ are N, and A²and A⁶ are independently CH or CR³. In some embodiments, A⁴ and A⁶ areN, and A² and A³ are independently CH or CR³. In some embodiments, A³and A⁶ are N, and A² and A⁴ are independently CH or CR³.

In some embodiments, A¹ and A⁶ are N. In some embodiments, A², A⁴, A⁵and A³ are independently CH or CR³. In some embodiments, A⁴ is N, andA², A⁵ and A³ are independently CH or CR³. In some embodiments, A⁵ is Nand A², A⁴ and A³ are independently CH or CR³. In some embodiments, A³is N, and A², A⁴ and A⁵ are independently CH or CR³. In someembodiments, A² and A⁴ are N, and A⁵ and A³ are independently CH or CR³.In some embodiments, A² and A⁵ are N, and A⁴ and A³ are independently CHor CR³. In some embodiments, A² and A³ are N, and A⁴ and A⁵ areindependently CH or CR³. In some embodiments, A⁴ and A⁵ are N, and A²and A³ are independently CH or CR³. In some embodiments, A⁴ and A³ areN, and A² and A⁵ are independently CH or CR³. In some embodiments, A⁵and A³ are N, and A² and A⁴ are independently CH or CR³.

In some embodiments, A² is N. In some embodiments, A¹ is CH or CR³. Insome embodiments, A³, A⁴, A⁵ and A⁶ are independently CH or CR³. In someembodiments, A³ is N, and A⁴, A⁵ and A⁶ are independently CH or CR³. Insome embodiments, A⁴ is N and A³, A⁵ and A⁶ are independently CH or CR³.In some embodiments, A⁵ is N, and A³, A⁴ and A⁶ are independently CH orCR³. In some embodiments, A⁶ is N, and A³, A⁴, and A⁵ are independentlyCH or CR³. In some embodiments, A³ and A⁴ are N, and A⁵ and A⁶ areindependently CH or CR³. In some embodiments, A³ and A⁵ are N, and A⁴and A⁶ are independently CH or CR³. In some embodiments, A³ and A⁶ areN, and A⁴ and A⁵ are independently CH or CR³. In some embodiments, A⁴and A⁵ are N, and A³ and A⁶ are independently CH or CR³. In someembodiments, A⁴ and A⁶ are N, and A³ and A⁵ are independently CH or CR³.In some embodiments, A⁵ and A⁶ are N, and A³ and A⁴ are independently CHor CR³.

In some embodiments, R¹ is phenyl. In some embodiments, R¹ istrifluoromethylphenyl. In some embodiments, R¹ is4-trifluoromethylphenyl. In some embodiments, R¹ is 4-fluorophenyl. Insome embodiments, R¹ is 4-chlorophenyl. In some embodiments, R¹ is4-methylphenyl. In some embodiments, R¹ is pyridyl optionallysubstituted with 1 to 3 R⁶.

In some embodiments, R² is phenyl optionally substituted with 1 to 4 R⁴.In some embodiments, R² is 5-membered heteroaryl optionally substitutedwith 1 to 4 R⁴. In some embodiments, R² is 6-membered heteroaryloptionally substituted with 1 to 4 R⁴. In some embodiments, R² is phenylsubstituted with 2 R⁴. In some embodiments, R² is 5-membered heteroarylsubstituted with 2 R⁴. In some embodiments, R² is 6-membered heteroarylsubstituted with 2 R⁴. In some embodiments, R² is phenyl substitutedwith 1 R⁴. In some embodiments, R² is 5-membered heteroaryl substitutedwith 1 R⁴. In some embodiments, R² is 6-membered heteroaryl substitutedwith 1 R⁴.

In some embodiments, R² is phenyl, chlorophenyl, methyl furan, In someembodiments, R² is selected from the group consisting of thiophene,thiazole, isoxazole, oxazole, 1,2,5-oxadiazole, pyrazole, pyrimidine andpyridazine, which are optionally substituted with methyl. In someembodiments, R² is pyridazine, isoxazole or oxazole.

In some embodiments, R² is 5- or 6-membered heteroaryl optionallysubstituted with 1 to 4 R⁴, wherein the heteroaryl comprises twoheteroatoms selected from N, O and S. In some embodiments, R² is 5- or6-membered heteroaryl optionally substituted with 1 to 4 R⁴, wherein theheteroaryl comprises two heteroatoms selected from N and S.

In some embodiments, R² is phenyl.

In some embodiments, R² is selected from the group consisting of:

In some embodiments, R² is

In some embodiments, R² is N

In some embodiments, R² is

In some embodiments of Formula VIIIa, VIIIb or VIIIc, R² is ethyl orisopropyl. In some embodiments of Formula VIIIa, VIIIb or VIIIc, R² is

In some embodiments, R² is R⁵ optionally substituted with 1 to 4 R⁴,wherein R⁵ is selected from the group consisting of furan, benzofuran,pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole,isothiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrrole, andpyrazole. In some embodiments, R² is R⁵ substituted with 1 R⁴. In someembodiments, R² is R⁵ substituted with 2 R⁴. In some embodiments, R² isR⁵ substituted with 3 R⁴. In some embodiments, R² is R⁵ substituted with4 R⁴.

In some embodiments, R⁴ is selected from the group consisting of loweralkyl (such as methyl), halo, lower haloalkyl, —OH, —OR⁷, cyano andphenyl optionally substituted methyl, wherein R⁷ is lower alkyl or lowerhaloalkyl.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, R³ is halo. In some embodiments, R³ is lower alkyl.

In some embodiments, n is 1.

In some embodiments, R⁶ is trifluoromethyl. In some embodiments, R⁶ isfluoro. In some embodiments, R⁶ is chloro. In some embodiments, R⁶ ismethyl. In some embodiments, R⁶ is cyano. In some embodiments, R⁶ is4-trifluoromethyl. In some embodiments, R⁶ is 4-fluoro. In someembodiments, R⁶ is 4-chloro. In some embodiments, R⁶ is 4-methyl. Insome embodiments, R⁶ is 4-cyano.

-   -   In some embodiments, the compound is selected from

-   -   or a tautomer, and/or pharmaceutically acceptable salt thereof.

In some embodiments, the group

in any of the above compounds is replaced with

In some embodiments, the compound is selected from

or a tautomer, and/or pharmaceutically acceptable salt thereof.

In some embodiments, the group

in any of the above compounds is replaced with

In some embodiments, the present technology provides a compound selectedfrom Table 2 or a tautomer, and/or pharmaceutically acceptable saltthereof:

TABLE 2 Compound Structure Name  4

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl) benzamide  5

2-chloro-N-(1-(4- (trifluoro- methyl)benzyl)-1H- indazol-3-yl) benzamide 9

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl) thiophene-2-carboxamide  10

4-methyl-N-(1-(4- (trifluoromethyl) benzyl)-1H- indazol-3-yl)thiazole-5- carboxamide  25

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl) isoxazole-5-carboxamide  28

4-methyl-N-(1-(4- (trifluoromethyl) benzyl)-1H- indazol-3-yl)isoxazole-5- carboxamide  31

5-methyl-N-(1-(4- (trifluoromethyl) benzyl)-1H- indazol-3-yl) oxazole-4-carboxamide  33

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl)- 1,2,5-oxadiazole-3-carboxamide  34

4-methyl-N-(1-(4- (trifluoromethyl) benzyl)-1H- indazol-3-yl) oxazole-5-carboxamide  35

3-methyl-N-(1-(4- (trifluoromethyl) benzyl)-1H- indazol-3-yl)isoxazole-4- carboxamide  36

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl) thiazole-5-carboxamide  39

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl) isothiazole-3-carboxamide  40

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl) oxazole-5-carboxamide  43

2-methyl-N-(1-(4- (trifluoromethyl) benzyl)-1H- indazol-3-yl)furan-3-carboxamide  44

3-methyl-N-(1-(4- (trifluoromethyl) benzyl)-1H- indazol-3-yl)-1H-pyrazole-4- carboxamide  49

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl) pyridazine-3-carboxamide  56

N-(1-(4-(trifluoro- methyl)benzyl)- 1H-indazol-3-yl) pyrimidine-5-carboxamide  64

N-(1-(4-chloro- benzyl)-1H-indazol- 3-yl)furan-3- carboxamide  65

N-(1-(4-chloro- benzyl)-1H-indazol- 3-yl)-3-methyl- isoxazole-4-carboxamide  66

N-(1-(4-chloro- benzyl)-1H-indazol- 3-yl)isoxazole-5- carboxamide  67

N-(1-(4-chloro- benzyl)-1H-indazol- 3-yl)-2-methyl- furan-3- carboxamide 68

N-(1-(4-chloro- benzyl)-1H-indazol- 3-yl)-4-methyl- thiazole-5-carboxamide  69

N-(1-(4-chloro- benzyl)-1H-indazol- 3-yl)pyridazine- 3-carboxamide  73

N-(1-(4-fluoro- benzyl)-1H-indazol- 3-yl)isoxazole-5- carboxamide  80

N-(1-(4-methyl- benzyl)-1H- indazol-3-yl) isoxazole-5- carboxamide 137

4-chloro-1-(4- (trifluoromethyl) benzyl)-1H- pyrazolo[3,4-c]pyridin-3-amine 138

N-(4-chloro-1-(4- (trifluoromethyl) benzyl)-1H- pyrazolo[3,4-c]pyridin-3-yl)-4- methylthiazole-5- carboxamide 139

N-(4-chloro-1-(4- (trifluoromethyl) benzyl)-1H- pyrazolo[3,4-c]pyridin-3- yl)pyridazine-3- carboxamide 151

N-(4-chloro-1-(4- (trifluoromethyl) benzyl)-1H- pyrazolo[3,4-c]pyridin-3- yl)propionamide 152

N-(4-chloro-1-(4- (trifluoromethyl) benzyl)-1H- pyrazolo[3,4-c]pyridin-3- yl)isobutyramide

In one aspect, the compound is not a compound of Formula I-j:

-   -   or a tautomer thereof, and/or a pharmaceutically acceptable salt        thereof, wherein        -   R²¹ is phenyl, 5-membered heteroaryl or 6-membered            heteroaryl, wherein the phenyl, 5-membered heteroaryl or            6-membered heteroaryl is optionally substituted with 1 to 3            R¹⁶;        -   L¹¹ is selected from the group consisting —(C(R¹⁸)₂)_(j)—,            —(C(R¹⁸)₂)_(q)—C(O)—(C(R¹⁸)₂)_(r)—,            —(C(R¹⁸)₂)_(q)—C(O)N(R¹⁸)—(C(R¹⁸)₂)_(r)—,            —(C(R¹⁸)₂)_(q)—N(R¹⁸)C(O)—(C(R⁸)₂)_(r)—,            —(C(R¹⁸)₂)_(q)—N(R¹⁸)S(O)₂—(C(R¹⁸)₂)_(r)—,            —(CH₂)_(q)—S(O)₂N(R¹⁸)—(CH₂)_(r)—, —S—, —O— and —NR¹⁸—;        -   q is 0 or 1;        -   r is 0 or 1;        -   L¹² is selected from the group consisting a covalent bond,            —C(O)N(R¹⁸)—, —N(R¹⁸)C(O)—, —N(R¹⁸)S(O)₂—, and            —S(O)₂N(R¹⁸)—;        -   R¹⁵ is phenyl, 5-membered heteroaryl, 6-membered heteroaryl,            5-membered heterocycloalkyl or 6-membered heterocycloalkyl;            wherein the phenyl, 5-membered heteroaryl or 6-membered            heteroaryl is optionally substituted with 1 to 4 R¹²,            wherein each R¹² is independently selected from the group            consisting of lower alkyl, lower haloalkyl, —OH, —OR¹⁷, —SH,            —SR¹⁷, —NR²⁰R²⁰, halo, cyano, nitro, —COH, —COR¹⁷, —CO₂H,            —CO₂R¹⁷, —CONR²⁰R²⁰, —OCOR¹⁷, —OCO₂R¹⁷, —OCONR²⁰R²⁰,            —NR²⁰COR²⁰, —NR²⁰CO₂R²⁰, —SOR¹⁷, —SO₂R¹⁷, —SO₂NR²⁰R²⁰, and            —NR²⁰SO₂R¹⁷;        -   each R¹⁶ is independently selected from the group consisting            of halo and lower alkyl (preferably methyl or ethyl)            optionally substituted with 1-3 halo; or two adjacent R¹⁶ on            a phenyl ring form a 5- or 6-membered cycloalkyl or            heterocycloalkyl fused with the phenyl ring;        -   R¹⁷ is lower alkyl (preferably methyl or ethyl);        -   R¹⁸ is hydrogen or lower alkyl (preferably methyl or ethyl);            and        -   each R²⁰ is independently hydrogen or lower alkyl            (preferably methyl or ethyl), or two R²⁰ together with the            atom(s) attached thereto form a 4- to 6-membered            heterocycloalkyl ring.

In one aspect, the compound is not a compound of Formula I-j:

-   -   or a tautomer thereof, and/or a pharmaceutically acceptable salt        thereof, wherein        -   R²¹ is phenyl, 5-membered heteroaryl or 6-membered            heteroaryl, wherein the phenyl, 5-membered heteroaryl or            6-membered heteroaryl is optionally substituted with 1 to 3            R¹⁶;        -   L¹ is selected from the group consisting —C(R¹⁸)₂—, —S—, —O—            and —NR¹⁸—;        -   L¹² is selected from the group consisting a covalent bond,            —C(O)N(R¹⁸)—, —N(R¹⁸)C(O)—, —N(R¹⁸)S(O)₂—, and            —S(O)₂N(R¹⁸)—;        -   R¹⁵ is phenyl, 5-membered heteroaryl, 6-membered heteroaryl,            5-membered heterocycloalkyl or 6-membered heterocycloalkyl;            wherein the phenyl, 5-membered heteroaryl or 6-membered            heteroaryl is optionally substituted with 1 to 4 R¹²,            wherein each R¹² is independently selected from the group            consisting of lower alkyl, lower haloalkyl, OH, OR¹⁷, SH,            SR¹⁷, NR²⁰R²⁰, halo, cyano, nitro, COH, COR¹⁷, CO₂H,            —CO₂R¹⁷, CONR²⁰R²⁰, OCOR¹⁷, OCO₂R¹⁷, OCONR²⁰R²⁰, NR²⁰COR²⁰,            —NR²⁰CO₂R²⁰, —SOR¹⁷, SO₂R¹⁷, —SO₂NR²⁰R²⁰, and NR²⁰SO₂R¹⁷;        -   each R¹⁶ is independently selected from the group consisting            of halo and lower alkyl (preferably methyl or ethyl)            optionally substituted with 1-3 halo;        -   R¹⁷ is lower alkyl (preferably methyl or ethyl);        -   R¹⁸ is hydrogen or lower alkyl (preferably methyl or ethyl);            and        -   each R²⁰ is independently hydrogen or lower alkyl            (preferably methyl or ethyl), or two R²⁰ together with the            atom(s) attached thereto form a 4- to 6-membered ring.            Methods of Treatment

In one aspect, the present technology provides a method of treating acondition or disorder mediated by fascin activity in a subject in needthereof which method comprises administering to the subject atherapeutically effective amount of a compound described herein.

In one embodiment the present technology provides a method of inhibitingfascin activity, comprising administering an effective amount of afascin inhibitor to a cell to thereby inhibit fascin activity in thecell, wherein the fascin inhibitor is a compound described herein. Insome embodiments, the fascin inhibitor has a fascin inhibition IC₅₀ ofno more than 100 μM. In some embodiments, the fascin inhibitor has afascin inhibition IC₅₀ of no more than 50 μM. In some embodiments, thefascin inhibitor has a fascin inhibition IC₅₀ of no more than 20 μM. Insome embodiments, the fascin inhibitor has a fascin inhibition IC₅₀ ofno more than 8 μM.

In some embodiments, the condition or disorder is a metastatic cancer, aneuronal disorder, neuronal degeneration, an inflammatory condition, aviral infection, a bacterial infection, lymphoid hyperplasia, Hodgkin'sdisease or ischemia-related tissue damage.

In some embodiments, the condition or disorder is a metastatic cancer.

In some embodiments, the cancer is a carcinoma, lymphoma, sarcoma,melanoma, astrocytoma, mesothelioma cells, ovarian carcinoma, coloncarcinoma, pancreatic carcinoma, esophageal carcinoma, stomachcarcinoma, lung carcinoma, urinary carcinoma, bladder carcinoma, breastcancer, gastric cancer, leukemia, lung cancer, colon cancer, centralnervous system cancer, melanoma, ovarian cancer, renal cancer orprostate cancer. In some embodiments, the cancer is lung cancer, breastcancer or prostate cancer.

In another aspect, the present technology provides is a method ofinhibiting fascin activity, comprising administering an effective amountof a fascin inhibitor to a cell to thereby inhibit fascin activity inthe cell, wherein the fascin inhibitor is a compound described herein.

In some embodiments, the cell is in an animal. In some embodiments, thecell has been removed from an animal. In some embodiments, the animal isa human. In some embodiments, the human suffers from a disease orcondition.

In some embodiments, the condition or disorder is a metastatic cancer, aneuronal disorder, neuronal degeneration, an inflammatory condition, aviral infection, a bacterial infection, lymphoid hyperplasia, Hodgkin'sdisease or ischemia-related tissue damage. In some embodiments, thecondition or disorder is a metastatic cancer.

In some embodiments, the cancer is a carcinoma, lymphoma, sarcoma,melanoma, astrocytoma, mesothelioma cells, ovarian carcinoma, coloncarcinoma, pancreatic carcinoma, esophageal carcinoma, stomachcarcinoma, lung carcinoma, urinary carcinoma, bladder carcinoma, breastcancer, gastric cancer, leukemia, lung cancer, colon cancer, centralnervous system cancer, melanoma, ovarian cancer, renal cancer orprostate cancer. In some embodiments, the cancer is lung cancer, breastcancer, or prostate cancer.

Agents that modulate the activity of fascin can be used to treat avariety of diseases and conditions. For example, as illustrated herein,fascin promotes actin bundling and plays a key role in cell migrationand metastasis of cancer cells. Hence, modulators and inhibitors offascin can be used to treat and inhibit metastatic cancer.

However, fascin also plays a role in other diseases and conditions. Forexample, neurite shape and trajectory is modulated by fascin (Kraft etal., Phenotypes of Drosophila brain neurons in primary culture reveal arole for fascin in neurite shape and trajectory, J. Neurosci,26(34):8734-47 (2006)). Fascin is also involved in neuronal degeneration(Fulga et al., Abnormal bundling and accumulation of F-actin mediatestau-induced neuronal degeneration in vivo Nat Cell Biol. 9(2):139-48(2007)). In addition, fascin plays a role in Hodgkin's disease (Pinkuset al., Fascin, a sensitive new marker for Reed-Sternberg cells ofHodgkin's disease, Am J Pathol. 150(2):543-562 (1997)). Fascin alsoplays a role in processing and presenting antigens, for example, onantigen presenting cells (Mosialos et al., Circulating human dendriticcells differentially express high levels of a 55-kd actin-bundlingprotein. Am. J. Pathol. 148(2):593-600 (1996); Said et al. The role offollicular and inter digitating dendritic cells in HIV-related lymphoidhyperplasia: localization of fascin. Mod Pathol. 10(5):421-27 (1997)).Moreover, fascin also plays a role in ischemic injury (Meller et al.,Ubiquitin proteasome-mediated synaptic reorganization: a novel mechanismunderlying rapid ischemic tolerance, J Neurosci. 28(1):50-9 (2008)).

Provided herein are agents that modulate fascin activity and that can beused for methods of treating and inhibiting metastatic cancer, neuronaldisorders, neuronal degeneration, inflammatory conditions, viralinfections, bacterial infections, lymphoid hyperplasia, Hodgkin'sdisease, and ischemia-related tissue damage.

Tumor metastasis is the major cause of death of cancer patients (Weiss2000, Fidler 2003). Thus, inhibition or prevention of tumor metastasiswill significantly increase the survival rate of cancer patients, allowmore moderate radiation or chemotherapy with less side-effects, andcontrol the progression of solid tumors.

Tumor cell migration and invasion are critical steps in the process oftumor metastasis (Partin et al. 1989, Aznavoorian et a. 1993, Condeeliset al. 2005). For cell migration to proceed, the actin cytoskeleton mustbe reorganized by forming polymers and bundles to affect the dynamicchanges of cell shapes (Jaffe et al. 2005, Matsudaira 1994, Otto 1994).Individual actin filaments are flexible and elongation of individualfilaments per se is insufficient for membrane protrusion which isnecessary for cell migration. Bundling of actin filaments providesrigidity to actin filaments for protrusion against the compressive forcefrom the plasma membrane (Mogilner et al. 2005).

One of the critical actin-bundling proteins is fascin. Fascin is theprimary actin cross-linker in filopodia, which are membrane protrusionscritical for the migration and metastasis of cancer cells. Fascin isrequired to maximally cross-link the actin filaments into straight,compact, and rigid bundles. Elevated expressions of fascin mRNA andprotein in cancer cells have been correlated with aggressive clinicalcourse, poor prognosis and shorter survival. Accordingly, metastaticcancer can be treated, prevented and/or inhibited by administeringfascin inhibitors as described herein.

In addition, a cancer at any stage of progression can be treated by themethod of the present technology, such as primary, metastatic, andrecurrent cancers. In some embodiments, cancers are treated beforemetastasis is detected, for example, to inhibit metastatic cancer fromdeveloping. In other embodiments, cancers are treated when metastasis isdetected, for example, to inhibit further metastasis and progression ofthe cancer.

Compounds described herein, or pharmaceutically acceptable saltsthereof, can also be used to treat autoimmune deficiencysyndrome-associated Kaposi's sarcoma, cancer of the adrenal cortex,cancer of the cervix, cancer of the endometrium, cancer of theesophagus, cancer of the head and neck, cancer of the liver, cancer ofthe pancreas, cancer of the prostate, cancer of the thymus, carcinoidtumors, chronic lymphocytic leukemia, Ewing's sarcoma, gestationaltrophoblastic tumors, hepatoblastoma, multiple myeloma, non-small celllung cancer, retinoblastoma, or tumors in the ovaries. A cancer at anystage of progression can be treated or detected, such as primary,metastatic, and recurrent cancers. Information regarding numerous typesof cancer can be found, e.g., from the American Cancer Society(www.cancer.org), or from, e.g., Wilson et al. (1991) Harrison'sPrinciples of Internal Medicine, 12th Edition, McGraw-Hill, Inc.

In some embodiments, method are provided for treating or inhibitingmetastatic cancer in an animal, for example, for human and veterinaryuses, which include administering to a subject animal (e.g., a human), atherapeutically effective amount of a compound described herein, orpharmaceutically acceptable salt thereof. In some embodiments, the cellhas been removed from an animal.

Treatment of, or treating, a disease or condition (e.g., cancer) isintended to include the alleviation of or diminishment of at least onesymptom typically associated with the disease or condition. Thetreatment also includes alleviation or diminishment of more than onesymptom of the disease or condition. The treatment may cure the diseaseor condition, for example, by eliminating the symptoms and/or the sourceof the disease or condition. For example, treatment can cure the cancerby substantially inhibiting metastasis of the cancer cells so thatremoval or killing of the primary tumor or cancer cell(s) substantiallyeliminates the cancer. Treatment can also arrest or inhibit themetastasis of the cancer and/or tumor cells without directly killing orpromoting the apoptosis of cancer cells.

Fascin functions in a variety of cellular functions that play criticalroles in modulating the growth, movement and interaction of cells.However the actin bundling function of fascin is directly involved intumor metastasis and invasive growth.

The anti-metastatic activity of fascin (e.g., in the presence of varioustest agents or therapeutic agents like those described herein) can beevaluated against varieties of cancers using methods described hereinand available to one of skill in the art. Anti-cancer activity, forexample, can be determined by identifying the dose that inhibits 50%cancer cell metastasis (IC₅₀) of a compound or composition as describedherein.

Also provided is a method for evaluating a therapeutically effectivedosage for treating a cancer (e.g., inhibiting metastasis) with acompound described herein, or pharmaceutically acceptable salt thereof,that includes determining the IC₅₀ of the agent in vitro. Such a methodpermits calculation of the approximate amount of agent needed per volumeto inhibit cancer cell migration. Such amounts can be determined, forexample, by standard microdilution methods. In some embodiments, thecompound or composition as described herein can be administered inmultiple doses over an extended period of time, or intermittently.

Compositions

The compounds (e.g., fascin inhibitors) as described herein can beformulated as pharmaceutical compositions and administered to amammalian host, such as a human patient in a variety of forms adapted tothe chosen route of administration, i.e., orally or parenterally, byintravenous, intramuscular, topical, transdermally, intrathecally,ocularly, intranasally, intraperitoneally or subcutaneous routes.

The compounds (e.g., fascin inhibitors) described herein may besystemically administered, e.g., orally, in combination with apharmaceutically acceptable vehicle such as an inert diluent or anassimilable edible carrier. They may be enclosed in hard or soft shellgelatin capsules, may be compressed into tablets, or may be incorporateddirectly with the food of the patient's diet. For oral therapeuticadministration, the active compound may be combined with one or moreexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.Such compositions and preparations should contain at least 0.1% ofactive compound. The percentage of the compositions and preparationsmay, of course, be varied and may conveniently be between about 2 toabout 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. A material used in preparing any unit dosageform should be pharmaceutically acceptable and substantially non-toxicin the amounts employed. In addition, the active compound may beincorporated into sustained-release preparations and devices.

The active compounds described herein may also be administeredintravenously or intraperitoneally by infusion or injection. Solutionsof the active compound or its salts can be prepared in water, optionallymixed with a nontoxic surfactant. Dispersions can also be prepared inglycerol, liquid polyethylene glycols, triacetin, and mixtures thereofand in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with severalof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds described herein, or pharmaceutically acceptablesalts thereof, to the skin are known to the art; for example, seeJacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No.4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S.Pat. No. 4,820,508).

Useful dosages of the compounds described herein, or pharmaceuticallyacceptable salts thereof, can be determined by comparing their in vitroactivity, and in vivo activity in animal models. Methods for theextrapolation of effective dosages in mice, and other animals, to humansare known to the art; for example, see U.S. Pat. No. 4,938,949.

Generally, the concentration of the compounds described herein, orpharmaceutically acceptable salts thereof, in a liquid composition, suchas a lotion, will be about 0.01 wt %, about 0.1 wt %, about 1.0 wt %,about 2.0 wt %, about 3.0 wt %, about 4.0 wt %, about 5.0 wt %, about10.0 wt %, about 25.0 wt %, or a range between and including any two ofthese values. The concentration in a semi-solid or solid compositionsuch as a gel or a powder will be about 0.01 wt %, about 0.1 wt %, about1.0 wt %, about 2.0 wt %, about 3.0 wt %, about 4.0 wt %, about 5.0 wt%, about 10.0 wt %, about 25.0 wt %, or a range between and includingany two of these values.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician. In general, however, a suitable dose will be in the range offrom about 1.0 to about 200 mg/kg, e.g., from about 1 to about 100 mg/kgof body weight per day, such as about 2.0 to about 100 mg/kg of bodyweight per day, such as about 3.0 to about 50 mg per kilogram bodyweight of the recipient per day, or in the range of about 5 to 20mg/kg/day. Alternatively, the compositions can be administered fivetimes a week on five consecutive days with a two day rest, or four timesa week on four consecutive days with a three day rest, or every otherday.

Methods for extrapolating effective dosages in mice and other animals,to humans are known in the art (See, for example, U.S. Pat. No.4,938,949). For example, in some embodiments, compounds describedherein, or pharmaceutically acceptable salts thereof, (for example thoseuseful for the treatment of colon and/or ovarian cancer) may beadministered at dosage levels of about 0.01 mg/kg to about 300 mg/kg,from about 0.1 mg/kg to about 250 mg/kg, from about 1 mg/kg to about 200mg/kg, from about 1 mg/kg to about 150 mg/kg, from about 1 mg/kg toabout 100 mg/kg, from about 1 mg/kg to about 90 mg/kg, from about 1mg/kg to about 80 mg/kg, from about 1 mg/kg to about 70 mg/kg, fromabout 1 mg/kg to about 60 mg/kg, from about 1 mg/kg to about 50 mg/kg,from about 1 mg/kg to about 40 mg/kg, from about 1 mg/kg to about 30mg/kg, from about 1 mg/kg to about 20 mg/kg, from about 5 mg/kg to about100 mg/kg, from about 5 mg/kg to about 90 mg/kg, from about 5 mg/kg toabout 80 mg/kg, from about 5 mg/kg to about 70 mg/kg, from about 5 mg/kgto about 60 mg/kg, from about 5 mg/kg to about 50 mg/kg, from about 5mg/kg to about 40 mg/kg, from about 5 mg/kg to about 30 mg/kg, fromabout 5 mg/kg to about 20 mg/kg, from about 10 mg/kg to about 100 mg/kg,from about 10 mg/kg to about 90 mg/kg, from about 10 mg/kg to about 80mg/kg, from about 10 mg/kg to about 70 mg/kg, from about 10 mg/kg toabout 60 mg/kg, from about 10 mg/kg to about 50 mg/kg, from about 10mg/kg to about 40 mg/kg, from about 10 mg/kg to about 30 mg/kg, fromabout 10 mg/kg to about 20 mg/kg, from about 20 mg/kg to about 100mg/kg, from about 20 mg/kg to about 90 mg/kg, from about 20 mg/kg toabout 80 mg/kg, from about 20 mg/kg to about 70 mg/kg, from about 20mg/kg to about 60 mg/kg, from about 20 mg/kg to about 50 mg/kg, fromabout 20 mg/kg to about 40 mg/kg, from about 20 mg/kg to about 30 mg/kg,of subject body weight per day, one or more times a day, to obtain thedesired therapeutic effect. In some embodiments, compounds may beadministered at a dosage of about 1 mg/kg or greater, 5 mg/kg orgreater; 10 mg/kg or greater, 15 mg/kg or greater, 20 mg/kg or greater,25 mg/kg or greater, 30 mg/kg or greater, 35 mg/kg or greater, 40 mg/kgor greater, 45 mg/kg or greater, 50 mg/kg or greater, 60 mg/kg orgreater, 70 mg/kg or greater, of body weight. It will also beappreciated that dosages smaller than 0.01 mg/kg or greater than 70mg/kg (for example 70-200 mg/kg) can be administered to a subject.

In some embodiments, the compounds described herein may be used inchemotherapy (i.e., to inhibit metastasis) and may be administered athigher dosage. For example, compounds to be used in chemotherapy may beadministered from about 100 mg/kg to about 300 mg/kg, from about 120mg/kg to about 280 mg/kg, from about 140 mg/kg to about 260 mg/kg, fromabout 150 mg/kg to about 250 mg/kg, from about 160 mg/kg to about 240mg/kg, of subject body weight per day, one or more times a day, toobtain the desired therapeutic effect.

In certain other embodiments, the compounds described herein may be usedin supportive therapy (e.g., as an adjuvant to surgery or irradiation ina range of common types of tumor) and may be administered at lowerdosage. For example, compounds to be used in supportive therapy may beadministered from about 1 mg/kg to about 30 mg/kg, from about 1 mg/kg toabout 25 mg/kg, from about 5 mg/kg to about 20 mg/kg, of subject bodyweight per day, one or more times a day, to obtain the desiredtherapeutic effect.

In certain other embodiments, the compounds described herein may be usedfor treating metastatic cancer (e.g., ovarian and/or colon cancer) andmay be administered at an intermediate dosage. For example, compounds tobe used in supportive therapy may be administered from about 1 mg/kg toabout 100 mg/kg, from about 1 mg/kg to about 80 mg/kg, from about 5mg/kg to about 70 mg/kg, from about 10 mg/kg to about 70 mg/kg, fromabout 10 mg/kg to about 60 mg/kg, from about 20 mg/kg to about 70 mg/kg,from about 20 mg/kg to about 60 mg/kg, of subject body weight per day,one or more times a day, to obtain the desired therapeutic effect.

The compound is conveniently administered in unit dosage form; forexample, containing 45 to 3000 mg, conveniently 90 to 2250 mg, mostconveniently, 450 to 1500 mg of active ingredient per unit dosage form.In some embodiments, the compound is administered at dosages of about 1to about 100 mg/kg.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 nM toabout 10 μM, or about 1 nM to 1 μM, or about 10 nM to about 0.5 μM. Thismay be achieved, for example, by the intravenous injection of a 0.05 to5% solution of the active ingredient, optionally in saline, or orallyadministered as a bolus containing about 20-2000 mg of the activeingredient. Desirable blood levels may be maintained by continuousinfusion to provide about 0.2 to 1.0 mg/kg/hr or by intermittentinfusions containing about 0.4 to 20 mg/kg of the active ingredient(s).The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

Compounds described herein, or pharmaceutically acceptable saltsthereof, are useful as therapeutic agents administered for inhibition ofcell migration and treatment of metastatic cancer. Such cancers includebut are not limited to, e.g., cancers involving the animal's head, neck,lung, mesothelioma, mediastinum, esophagus, stomach, pancreas,hepatobiliary system, small intestine, colon, colorectal, rectum, anus,kidney, ureter, bladder, prostate, urethra, penis, testis, gynecologicalorgans, ovaries, breast, endocrine system, skin, or central nervoussystem. Thus, for example, the cancer can be a breast cancer, aleukemia, a lung cancer, a colon cancer, a central nervous systemcancer, a melanoma, an ovarian cancer, a renal cancer, or a prostatecancer.

Additionally, compounds described herein, or pharmaceutically acceptablesalts thereof, such as the exemplary salts described herein, may beuseful as pharmacological tools for the further investigation of theinhibition of cell migration.

The compounds described herein, or pharmaceutically acceptable saltsthereof, can also be administered in combination with other therapeuticagents that are effective for treating or controlling the spread ofcancerous cells or tumor cells.

Moreover, the compounds described herein, or pharmaceutically acceptablesalts thereof, can be tested in appropriate animal models. For example,the compounds described herein, or pharmaceutically acceptable saltsthereof, can be tested in animals with known tumors, or animals thathave been injected with tumor cells into a localized area. The degree ornumber of secondary tumors that form over time is a measure ofmetastasis and the ability of the compounds to inhibit such metastasiscan be evaluated relative to control animals that have the primary tumorbut receive no test compounds.

The compounds described herein, or pharmaceutically acceptable saltsthereof, will also find use in treatment of brain disorders (Kraft etal., J. Neurosci. 2006 Aug. 23; 26(34):8734-47); Hodgkin's disease(Pinkus et al., Am J Pathol. 1997 February; 150(2):543-62); virusinfection (Mosialos et al., Am J Pathol. 1996 February; 148(2):593-600);neuronal degeneration (Fulga et al., Nat Cell Biol. 2007 February: 9(2):139-48); lymphoid hyperplasia (Said et al., Mod Pathol. 1997 May;10(5):421-7); and ischemia (Meller et al., J Neurosci. 2008 Jan. 2;28(1):50-9.)

General Synthetic Methods

The compounds described herein are commercially available or can beprepared from readily available starting materials using the followinggeneral methods and procedures. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Third Edition, Wiley, New York, 1999, and references citedtherein.

Furthermore, the compounds described herein may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers, or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis invention, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures, orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989),Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley and Sons, 4^(th) Edition), andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

The various starting materials, intermediates, and compounds describedherein may be isolated and purified where appropriate using conventionaltechniques such as precipitation, filtration, crystallization,evaporation, distillation, and chromatography. Characterization of thesecompounds may be performed using conventional methods such as by meltingpoint, mass spectrum, nuclear magnetic resonance, and various otherspectroscopic analyses.

Amide coupling reagents are known in the art and may include, but arenot limited to, amininum and phosphonium based reagents. Aminium saltsincludeN-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU),N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HBTU),N-[(1H-6-chlorobenzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HCTU),N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminiumtetrafluoroborate N-oxide (TBTU), andN-[(1H-6-chlorobenzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminiumtetrafluoroborate N-oxide (TCTU). Phosphonium salts include7-azabenzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyAOP) andbenzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP). Amide formation step may be conducted in a polar solvent suchas dimethylformamide (DMF) and may also include an organic base such asdiisopropylethylamine (DIEA) or dimethylaminopyridine (DMAP).

Cross-coupling reactions are well known in the art and, for example, arereported in Anna Roglans, et al. Diazonium Salts as Substrates inPalladium-Catalyzed Cross-Coupling Reactions, Chem. Rev., 2006, 106(11):4622-4643; Brad M. Rosen, et al., Nickel-Catalyzed Cross-CouplingsInvolving Carbon-Oxygen Bonds, Percec Chem. Rev., 2011, 111(3):1346-1416; Jean-Pierre Corbet, et al., Selected PatentedCross-Coupling Reaction Technologies, Chem. Rev., 2006, 106(7):2651-2710; Gwilherm Evano et al., Copper-Mediated Coupling Reactionsand Their Applications in Natural Products and Designed BiomoleculesSynthesis, Chem. Rev., 2008, 108 (8):3054-3131; Benny Bogoslavsky, etal., Formation of a Carbon-Carbon Triple Bond by Coupling Reactions InAqueous Solution, Science 308 (5719): 234-235 (2005); and M. Lafrance,et al., Catalytic Intermolecular Direct Arylation of Perfluorobenzenes,J. Am. Chem. Soc. 128 (27): 8754-8756 (2006); Norio Miyaura, et al., “Anew stereospecific cross-coupling by the palladium-catalyzed reaction of1-alkenylboranes with 1-alkenyl or 1-alkynyl halides,” TetrahedronLetters, 1979, 20(36): 3437-3440; P. E. Fanta, “The Ullmann Synthesis ofBiaryls”, Synthesis, 1974, 1974: 9-21; M. Gomberg, and W. E. Bachmann,J. Am. Chem. Soc., 1924, 42(10):2339-2343; R. J. P. Corriu and Masse, J.P. “Activation of Grignard reagents by transition-metal complexes. A newand simple synthesis of trans-stilbenes and polyphenyls,” Journal of theChemical Society, Chemical Communications, 1972, (3):144a.

In some aspects, compounds of Formula I can be prepared according toScheme 1 or other methods described herein.

In some aspects, compounds of Formula IIIa wherein R³ is hydrogen(Compound 2-3) can be prepared from 1H-indazol-3-amine (Compound 2-1,available from e.g., Enamine LLC) according to Scheme 2 or other methodsdescribed herein.

In some aspects, compounds of Formula VIIIa wherein R³ is 4-chloro(Compound 3-2 or 3-3) from 4-chloro-1H-pyrazolo[3,4-c]pyridin-3-amine(Compound 3-1, available from, e.g., Novasyn Organics PVT. Ltd.) can beprepared according to Scheme 3 or other methods described herein.Compounds of formula 2-4 are generally available from commercial sourcesor can prepared by methods known in the art. For example,4-(bromomethyl)benzonitrile, 3-(bromomethyl)benzonitrile, 2-fluorobenzylbromide, 3-fluorobenzyl bromide, 3-chlorobenzyl bromide, 4-chlorobenzylbromide, 4-fluorobenzyl bromide, 4-methylbenzyl bromide,3,4-difluorobenzyl bromide and 2,3-difluoro-4-methylbenzyl bromide,etc., are available from Sigma-Aldrich Co. LLC.

All publications, patent applications, issued patents, and otherdocuments referred to in this specification are herein incorporated byreference as if each individual publication, patent application, issuedpatent, or other document was specifically and individually indicated tobe incorporated by reference in its entirety. Definitions that arecontained in text incorporated by reference are excluded to the extentthat they contradict definitions in this disclosure.

The present technology, thus generally described, will be understoodmore readily by reference to the following Examples, which is providedby way of illustration and is not intended to be limiting of the presenttechnology. Other compounds were or may be prepared similarly or bymethods known in the art.

EXAMPLES Example 1: Compound Preparation

Preparation of Intermediate 1:1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-amine

A mixture of KOH (6.95 g, 124 mmol) in DMSO (165 mL) was stirred at roomtemperature for 5 min. 1H-indazol-3-amine (8.25 g, 62.0 mmol) was thenadded in one portion. The resulting mixture was stirred at roomtemperature for 5 min. A solution of 4-trifluoromethylbenzyl bromide(15.6 g, 65.1 mmol) in DMSO (83 ml) was then added dropwise over 30 min.When the addition was complete, the resulting mixture was stirred atroom temperature for an additional 1 h. The mixture was quenched by theaddition of water (200 mL). The mixture was then extracted with CH₂Cl₂(3×100 mL). The combined extracts were washed with H₂O (2×100 mL), brine(1×100 mL), then dried over MgSO₄, filtered and concentrated in vacuo.Purification by flash chromatography (Silica, 200 g, 10-100%EtOAc/Hexanes) gavel-(trifluoromethylbenzyl)-1H-indazol-3-amine (21.79g, 56.6 mmol, 91.3% yield) as an off-white crystalline solid. MS (ESI)m/z: 292 (M+H)+

Preparation of Compound 1:4,5-dimethyl-N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide

To a solution of intermediate 1 (29.2 mg, 0.10 mmol),4,5-dimethylfuran-2-carboxylic acid (15.4 mg, 0.11 mmol), andtriethylamine (45.2 μL, 0.30 mmol) in dichloromethane (2 mL) was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (118.6μL, 0.20 mmol). The resulting reaction mixture was stirred at room tempfor 3 h and then the solvent was removed.

The crude product was purified by Prep. HPLC (sunfire 5μ 100 mm column,MeOH/H₂O as solvents). 26 mg of 4,5-dimethyl-N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide obtained as a solid. MS(ESI) m/z: 414 (M+H)+

Preparation of Compounds 2 to 47 and 49 to 56 in Table 1

These compounds were prepared by following procedures similar to thatdescribed above in a similar yield.

Preparation of Intermediate 2: N-(1H-indazol-3-yl)furan-3-carboxamide

To a solution of 1H-indazol-3-amine (1.33 g, 10 mmol),furan-2-carboxylic acid (1.23 g, 11 mmol), and triethylamine (452 μL, 30mmol) in dichloromethane (20 mL) was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.12mL, 20 mmol). The resulting reaction mixture was stirred at room tempfor 3 h and then the solvent was removed. The crude product was purifiedby flash chromatography (Silica, 100 g, 10-100% EtOAc/DCM) gaveN-(1H-indazol-3-yl)furan-3-carboxamide (1.27 g, 5.6 mmol, 56% yield) asa white crystalline solid. MS (ESI) m/z: 228 (M+H)+

C: Preparation of Compound 48:N-(1-(3-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-3-carboxamide

A mixture of KOH (11.2 mg, 0.20 mmol) in DMSO (1 mL) was stirred at roomtemperature for 5 min. intermediate 2 (22.7 mg, 0.10 mmol) was thenadded in one portion. The resulting mixture was stirred at roomtemperature for 5 min. A solution of 3-trifluoromethylbenzyl bromide(23.9 mg, 0.10 mmol) in DMSO (1 mL) was then added dropwise. Theresulting reaction mixture was stirred at room temperature overnight.The crude product was purified by Prep. HPLC (sunfire 5μ 100 mm column,MeOH/H₂O as solvents). 12 mg ofN-(1-(3-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-3-carboxamideobtained as a solid. MS (ESI) m/z: 386 (M+H)+

D: Preparation of Compounds 57 and 58

Compounds 57 and 58 were prepared by following procedures similar tothat described for making compound 48 in a similar yield.

E: Preparation of Compound 91:1-((6-(trifluoromethyl)pyridine-3-yl)methyl)-1H-indazol-3-amine

A mixture of KOH (6.95 g, 124 mmol) in DMSO (165 mL) was stirred at roomtemperature for 5 min. 1H-indazol-3-amine (8.25 g, 62.0 mmol) was thenadded in one portion. The resulting mixture was stirred at roomtemperature for 5 min. A solution of5-(chloromethyl)-2-(trifluoromethyl)pyridine (12.7 g, 65.1 mmol) in DMSO(83 mL) was then added dropwise over 30 min. When the addition wascomplete, the resulting mixture was stirred at room temperature for anadditional 1 h. The mixture was quenched by the addition of water (200mL). The mixture was then extracted with CH₂Cl₂ (3×100 mL). The combinedextracts were washed with H₂O (2×100 mL), brine (1×100 mL), then driedover MgSO₄, filtered and concentrated in vacuo. Purification by flashchromatography (Silica, 200 g, 10-100% EtOAc/Hexanes) gave1-((6-(trifluoromethyl)pyridine-3-yl)methyl)-1H-indazol-3-amine (14.9 g,50.9 mmol, 82% yield) as an off-white crystalline solid. MS (ESI) m/z:293 (M+H)⁺.

F: Preparation of Compound 92:N-(1-((6-(trifluoromethyl)pyridine-3-yl)methyl)-1H-indazol-3-yl)furan-3-carboxamide

To a solution of example 91 (29.3 mg, 0.10 mmol), furan-3-carboxylicacid (15.4 mg, 0.11 mmol), and triethylamine (45.2 μl, 0.30 mmol) inDichloromethane (2 mL) was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (118.6μl, 0.20 mmol). The resulting reaction mixture was stirred at room tempfor 3 h and then the solvent was removed. The crude product was purifiedby Prep. HPLC (sunfire 5u 100 mm column, MeOH/H₂O as solvents). 26 mg ofN-(1-((6-(trifluoromethyl)pyridine-3-yl)methyl)-1H-indazol-3-yl)furan-3-carboxamidewas obtained as a solid. MS (ESI) m/z: 387 (M+H)⁺.

G: Preparation of Compounds 93-142

Additional examples (93 to 142) were prepared by procedures similar tothat described for making Example 91 and 92 in a similar yield.

H: Preparation of Compound 149:1-(4-(trifluoromethyl)benzyl)-4-chloro-1H-pyrazolo(3,4-c)pyridine-3-methylamine

To a solution of example 137 (32.6 g, 0.10 mmol) in THF (2 mL) was addediodomethane (42.6 mg, 0.30 mmol), and triethylamine (30.5 mgl, 0.30mmol). The resulting reaction mixture was sealed and heated at 100degree for 3 days and then the solvent was removed. The crude productwas purified by Prep. HPLC (sunfire 5u 100 mm column, MeOH/H₂O assolvents) to yield1-(4-(trifluoromethyl)benzyl)-4-chloro-1H-pyrazolo(3,4-c)pyridine-3-methylamine(16 mg, 0.047 mmol, 47% yield) as a gum. MS (ESI) m/z: 341 (M+H)+.

I: Preparation of Compound 150:N-(1-(4-(trifluoromethyl)benzyl)-4-chloro-H-pyrazolo(3,4-c)pyridyl)-3-acetamide

To a solution of example 137 (32.6 g, 0.10 mmol) in THF (2 mL) was addedacetyl chloride (15.6 mg, 0.20 mmol), and triethylamine (30.5 mgl, 0.30mmol). The resulting reaction mixture was stirred at room temperaturefor 5 hours and then the solvent was removed. The crude product waspurified by Prep. HPLC (sunfire 5u 100 mm column, MeOH/H₂O as solvents)to yieldN-(1-(4-(trifluoromethyl)benzyl)-4-chloro-1H-pyrazolo(3,4-c)pyridyl)-3-acetamide(23 mg, 0.0625 mmol, 62.5% yield) as a white solid MS (ESI) m/z: 369(M+H)⁺.

J. Preparation of Compounds 151 to 153

The examples 151 to 153 were prepared by procedures similar to thatdescribed for making Example 150 in a similar yield.

K. Preparation of Compound 143:3-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indazole

A mixture of KOH (1.12 g, 20 mmol) in DMSO (50 mL) was stirred at roomtemperature for 5 min. 3-bromo-1H-indazole (1.97 g, 10 mmol) was thenadded in one portion. The resulting mixture was stirred at roomtemperature for 5 min. A solution of1-(bromomethyl)-4-(trifluoromethyl)benzene (3.6 g, 15 mmol) in DMSO (5mL) was then added dropwise over 10 min. When the addition was complete,the resulting mixture was stirred at room temperature for an additional1 h. The mixture was quenched by the addition of water (200 mL). Themixture was then extracted with CH₂Cl₂ (3×100 mL). The combined extractswere washed with H₂O (2×100 mL), brine (1×100 mL), then dried overMgSO₄, filtered and concentrated in vacuo. Purification by flashchromatography (Silica, 200 g, 10-100% EtOAc/Hexanes) gave3-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indazole (3.1 g, 8.7 mmol, 87%yield) as an off-white crystalline solid. MS (ESI) m/z: 355 and 357(M+H)⁺.

L: Preparation of Compound 144:3-Phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indazole

Cesium carbonate (65 mg, 0.20 mmol),3-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indazole (35.6 mg, 0.10 mmol),phenylboronic acid (18.2 mg, 0.15 mmol) and PdCl₂(dppf) (7.2 mg, 0.01mmol) were suspended in dioxane (5 mL) and degassed with argon for 5minutes. The reaction was sealed and heated at 90 degree overnight. Thecrude product was purified by Prep. HPLC (sunfire 5u 100 mm column,MeOH/H₂O as solvents). 23 mg of3-Phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indazole was obtained as asolid. MS (ESI) m/z: 353 (M+H)+.

M: Preparation of Compounds 145-148

The examples 145 to 148 were prepared by procedures similar to thatdescribed for making Example 144 in a similar yield.

Example 2: Human Fascin-1 Expression and Purification

Recombinant human fascin 1 was expressed as a GST fusion protein in BL21Escherichia coli. One liter of 2YT medium with ampicillin was inoculatedovernight with 3 mL of BL21/DE3 culture transformed with pGEX4T-fascin 1plasmid and grown at 37° C. until attenuance at 600 nm (D₆₀₀) reachedabout 0.8. The culture was then transferred to 18° C. and induced by theaddition of 0.1 mM isopropyl β-d-thiogalactoside (IPTG) for 12 h.Bacteria were harvested by centrifugation at 5,000 r.p.m. for 10 min.The pellets were suspended in 30 mL of PBS supplemented with 0.2 mMPMSF, 1 mM DTT, 1% (v/v) Triton X-100 and 1 mM EDTA. After sonication,the suspension was centrifuged at 15,000 r.p.m. for 30 min to remove thecell debris. The supernatant was then incubated for 2 h with 4 mL ofglutathione beads (Sigma) at 4° C. After extensive washing with PBS, thebeads were resuspended in 10 mL of thrombin cleavage buffer (20 mMTris-HCl pH 8.0, 150 mM NaCl, 2 mM CaCl₂, 1 mM DTT). Fascin was releasedfrom the beads by incubation overnight with 40-100 U of thrombin at 4°C. After centrifugation, 0.2 mM PMSF was added to the supernatant toinactivate the remnant thrombin activity. The fascin protein was furtherconcentrated with a Centricon® (Boca Raton, Fla.) filter to about 50mg/mL.

Example 3: Quantification of Fascin Expression Levels

The levels of fascin mRNA and protein can be determined by real-time PCRand Western blot, respectively. For quantitative real-time PCR, samplesfrom cancer patients were used for RNA isolation. Oligonucleotideprimers specific for fascin mRNA were used for PCR reactions. ForWestern blots, samples from cancer patients were assessed withanti-fascin antibody. The intensity of the bands representing fascinproteins was quantified by image documentation and quantificationsoftware.

Example 4: Compound Analysis

Representative compounds described herein were tested for fascininhibition activity. Purified fascin protein (15 μL of 0.5 μM) in buffer(100 mM KCl, 20 mM Tris/HCl, pH 7.5, 2 mM MgCl₂) was added into eachwell of a clear 384-well flat-bottom plate (Corning) using ThermoMultidrop Combi (Fisher). Compound solutions (5 mM stock, 180 nL) werepin transferred from stock 384-well plates into the 384-well assayplates and incubated for 30 min. Then 15 μL of 0.5 μM polymerized actin(in 100 mM KCl, 20 mM Tris/HCl, pH 7.5, 2 mM MgCl₂, 1 mM DTT, 1 mM ATP)(Cytoskeleton Inc.) was added, resulting in 30 μM final concentrationfor chemical compounds. After another 30 min, 10 μL of Alexa Fluro 488Phalloidin (25 times dilution from stocks in 100% methanol, Invitrogen)was added to stain F-actin and was incubated in the dark for one hour.Mixed solution (25 μL) was then transferred to one well in a black384-well plate coated with poly-D-lysine, and stained actin bundles orF-actin would stick onto the poly-D-lysine plates. After the plates werethoroughly washed with 1×PBS for 3 times, the plate was imaged using anImageXpress Micro High Content Screening System (Molecular devices). Theimages were processed and analyzed using MetaMorph software. The rawimage data for each well was background-corrected by subtraction of themedian intensities across all wells on the plate. Thebackground-corrected data was used to compute the bundle length for eachwell. The negative control wells were employed for quality control:multiple DMSO-only control wells (16 wells/plate) were present on eachassay plate.

In confirmative screening of the compounds, a control with anotheractin-bundling protein, fimbrin, can used to eliminate compounds thatare not specific to fascin. Also in confirmative screening, eachcompound can be tested in duplicate on the same plate.

The % inhibition values of certain compounds are shown in Table 1 above.

Example 5: Boyden-Chamber Cell Migration Assay

Boyden chamber assays for cell migration can be used to show theactivity of the compounds described herein in inhibiting the migrationof tumor cells, such as breast tumor cells, prostate tumor cells, andlung tumor cells. Certain tumor cells with fascin expression are listedbelow.

4T1 breast tumor cells MDA-MB-231 breast tumor cells DU145 prostatetumor cells PC-3 prostate tumor cells LLC lung tumor cells

Exemplifying procedure: MDA-MB-231 cells (5×10⁴) or 4T1 Cells (1×10⁵)were suspended in 100 μl starvation medium and added to the upperchamber of an insert (6.5 mm diameter, 8 μm pore size; Becton Dickson).The insert was placed in a 24-well plate containing 700 μL starvationmedium with or without 10% FBS. When used, inhibitors were added to thelower chamber. Migration assays were performed for 6 h and cells arefixed with 3.7% formaldehyde. Cells were stained with crystal violetstaining solution, and cells on the upper side of the insert wereremoved with a cotton swab. Three randomly selected fields (×10objectives) on the lower side of the insert were photographed, and themigrated cells were counted. Migration was expressed as average numberof migrated cells in a field.

The following are the IC₅₀ data of selected compounds when tested usingMDA-MB-231 human breast tumor cells.

Compound 10: 31 μM

Compound 25: 54 μM

Compound 35: 18 μM

Compound 43: 12 μM

Compound 49: 13 μM

Compound 65: 64 μM

Compound 66: 161 μM

In vitro data obtained in such assays are known to correlate withresults obtained from in vivo models. See, e.g., Shan, D., et al.,Synthetic analogues of migrastatin that inhibit mammary tumor metastasisin mice, Proc. Nat. Acad. Sci. 102: 3772-3776 (2005).

Example 6: Tumor Metastasis in Mouse Models

Tumor cell migration is essential for tumor metastasis. Representativecompounds described herein were investigated their effects on tumormetastasis in an animal model. Tumor cells (4T1 breast tumor cells) wereinjected into the mammary fat-pad of mice. The metastasis of thesebreast tumor cells from the mammary gland to the lung was monitored bythe clonogenic assay.

Balb/c mice were purchased from Charles River. All animal procedureswere approved by the Animal Care and Use Committees of the Weill CornellMedical College and performed in accordance with institutional polices.For xenograft tumor metastasis studies, 5×10⁵ 4T1 cells were suspendedin 100 μL PBS and injected subcutaneously into the mammary glands of 6-8week old female Balb/c mice. Tumor incidence was monitored for 21 daysafter injection. Tumor size was measured three times a week, and thevolume was calculated using the formula length×width²×0.5. Compoundtreatment was initiated 7 days after tumor implantation; animals wereadministered daily with indicated dose for 2 weeks. On day 28, the micewere sacrificed. Numbers of metastatic 4T1 cells in lungs weredetermined by the clonogenic assay. In brief, lungs were removed fromeach mouse on day 28, finely minced and digested for 2 h at 37° C. in 5mL of enzyme cocktail containing PBS and 1 mg/mL collagenase type IV ona rocker. After incubation, samples were filtered through 70-μm nyloncell strainers and washed twice with PBS. Resulting cells weresuspended, plated with a series of dilutions in 10-cm tissue culturedishes in RPMI-1640 medium containing 60 μM thioguanine, metastasizedtumor cells formed foci after 14 days, at which time they were fixedwith methanol and stained with 0.03% methylene blue for counting. Datawere expressed as mean±S.D. and analyzed by Student's t test withsignificance defined as p<0.05.

When tested in this animal model at 100 mg/kg, Compounds 10 and 43showed more than 90% inhibition of tumor metastasis. The compoundsdescribed herein are contemplated to be useful for treating a conditionor disorder mediated by fascin activity and/or tumor metastasis.

Example 7: In Vivo Mouse Model for Prostate Tumor Metastasis

5- to 6-week-old male severe combined immunodeficient mice (n=20)purchased from Charles River (Wilmington, Mass.) are randomly dividedinto two groups (n=10 animals per group). In both two groups, humanprostate tumor cells PC-3Luc cells (stably transfected with luciferasegene) (2×10⁵ cells in 100 μl of Dulbecco phosphate-buffered saline [PBS]lacking Ca²⁺ and Mg²⁺) are introduced into animals by intracardiacinjection under 1.75% isoflurane/air anesthesia. Throughout the durationof the experiment, animals in group 1 receive daily testing compoundsadministered intraperitoneally (i.p.) in 0.2 mL of sterile physiologicalsaline beginning 1 week before tumor cell inoculation. In group 2(untreated control), animals receive a daily 0.2 mL i.p. injection ofthe vehicle, sterile physiological saline. Mice are serially imagedweekly for 5 weeks using an IVIS system (Xenogen Corp, Alameda, Calif.),and the results are analyzed using Living Image software (Xenogen). Forimaging, mice are injected with luciferin (40 mg/mL) i.p., and ventralimages are acquired 15 minutes after injection under 1.75%isoflurane/air anesthesia. At the end of the experiments, animals arekilled, and tissue is collected for histopathologic confirmation of bonemetastasis. It is contemplated that less bone metastasis is found ingroup 1 animals treated with a fascin inhibitory compound disclosedherein as compared with that found in group 2 animals. As such the testcompounds are useful for treating cancer, in particular, prostate tumormetastasis.

Example 8: In Vivo Mouse Model for Lung Tumor Metastasis

20 mice are divided into two groups, and 2×10⁶ A⁵⁴⁹ human lung tumorcells are injected into each mouse via the tail vein. One group istreated with a compound disclosed herein and another group is used ascontrol. After 8 weeks, the lungs are harvested, fixed, and embedded inparaffin. The number of metastatic lung nodules is counted in serialhistological sections stained with H&E. The areas of metastatic lungnodules are measured in scanned images of the H&E-stained tumor sectionsusing Paint.NET software. It is contemplated that the number and area ofmetastatic lung nodules in the treated animals are smaller than that ofthe untreated control animals. As such the test compounds are useful fortreating cancer, in particular, lung tumor metastasis.

Example 9: Treatment of Tumor Metastasis in Human

Human patients having metastatic breast cancer are administeredintravenously with a fascin inhibitory compound disclosed herein orplacebo in a randomized open-label trial. The patients are separatedinto 5 groups. Patients in each group are administered a daily dosage of0 mg (placebo), 100 mg, 200 mg, 500 mg, or 1000 mg of the compound,respectively, in 3-week cycles. The time to disease progression, overallresponse rate (ORR), duration of response, and overall survival (OS)rate are measured at the end of each cycle with known techniques. It iscontemplated that patients administered with the fascin inhibitorycompound have a longer mean or average time to disease progressionand/or duration of response, a higher mean or average overall responserate and/or overall survival rate, than patients administered withplacebo. Fewer new tumors distant from the original tumor site aredeveloped in patients administered with fascin inhibitory compound thanin patients administered with placebo. In a preferred embodiment, one ormore of the results are dose-responsive. Side effects are monitored andrecorded. As such the test compounds are useful for treating tumormetastasis in human.

REFERENCES

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EQUIVALENTS

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms ‘comprising,’ ‘including,’ ‘containing,’ etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase ‘consisting essentially of’ will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase ‘consisting of’excludes any element not specified.

The present disclosure is not to be limited in terms of the particularembodiments described in this application, which are intended asillustrations of various aspects. Many modifications and variations canbe made without departing from its spirit and scope, as will be apparentto those skilled in the art. Functionally equivalent compositions,apparatuses, and methods within the scope of the disclosure, in additionto those enumerated herein, will be apparent to those skilled in the artfrom the foregoing descriptions. Such modifications and variations areintended to fall within the scope of the appended claims. The presentdisclosure is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled. It is to be understood that this disclosure is not limited toparticular methods, reagents, compounds compositions or biologicalsystems, which can, of course, vary. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as ‘up to,’ ‘at least,’ ‘greater than,’ ‘less than,’ and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

While certain embodiments have been illustrated and described, it shouldbe understood that changes and modifications can be made therein inaccordance with ordinary skill in the art without departing from thetechnology in its broader aspects as defined in the following claims.

What is claimed:
 1. A compound of Formula I:

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;wherein A³ and A⁶ are independently CH, CR³ or N, and at least one of A³and A⁶ is N; R¹ is phenyl, 5-membered heteroaryl or 6-memberedheteroaryl, wherein the phenyl, 5-membered heteroaryl or 6-memberedheteroaryl is optionally substituted with 1 to 3 R⁶; L² is selected fromthe group consisting of —C(O)NH—, —NHC(O)—, —C(O)CH₂—, —CH₂C(O)—,—NHCH₂—, and —CH₂NH—; R² is 6- to 10-membered aryl or 5- to 10-memberedheteroaryl; wherein the 6- to 10-membered aryl or 5- to 10-memberedheteroaryl is optionally substituted with 1 to 4 R⁴, wherein each R⁴ isindependently selected from the group consisting of lower alkyl, lowerhaloalkyl, and halo; each R³ is independently selected from the groupconsisting of lower alkyl, lower haloalkyl, —OH, —OR⁷, —SH, —SR⁷, halo,cyano, nitro, —COH, —COR⁷, —CO₂H, —CO₂R⁷, —CONR¹⁰R¹⁰, —OCOR⁷, —OCO₂R⁷,—OCONR¹⁰R¹⁰, —NR¹⁰COR¹⁰, —NR¹⁰CO₂R¹⁰, —SOR⁷, —SO₂R⁷, —SO₂NR¹⁰R¹⁰, and—NR¹⁰SO₂R⁷; m is 0, 1, or 2; each R⁶ is independently selected from thegroup consisting of halo, cyano, lower alkyl and lower haloalkyl; R⁷ islower alkyl or lower haloalkyl; and each R¹⁰ is independently hydrogenor lower alkyl, or two R¹⁰ together with the atom(s) attached theretoform a 4- to 6-membered ring; provided that the compound is notN-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide,wherein one or more hydrogen is optionally replaced by a deuterium. 2.The compound of claim 1, wherein R¹ is phenyl optionally substitutedwith 1 to 3 R⁶.
 3. The compound of claim 1, wherein L² is selected fromthe group consisting of —C(O)NH— and —NHC(O)—.
 4. The compound of claim1, wherein R² is the 5- to 10-membered heteroaryl.
 5. The compound ofclaim 1, wherein m is 1 or
 2. 6. The compound of claim 1, wherein R^(e)is optionally substituted with 1 to 4 R⁴, and R² is selected from thegroup consisting of furan, benzofuran, pyridine, pyridazine, pyrazine,thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole,imidazole, pyrrole, and pyrazole.
 7. The compound of claim 1, wherein R⁴is not optional and is selected from the group consisting of loweralkyl, halo, lower haloalkyl, —OH, —OR⁷, cyano and phenyl optionallysubstituted methyl, and wherein R⁷ is lower alkyl or lower haloalkyl. 8.A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 9. The compound of claim 1, whereinR² is selected from the group consisting of


10. The compound of claim 1, wherein A³ is N.
 11. The compound of claim1, wherein A⁶ is N.